I I CS Health Care Guideline: Diagnosis and Management of Type …a... · 2010-09-21 · • the ICSI Health Care Guideline may be adopted or adapted for use within the medical group

Health Care Guideline:

Diagnosis and Management of Type 2 Diabetes Mellitus in Adults

Thirteenth Edition May 2009

I ICSI NSTITUTE FOR C LINICAL S YSTEMS I MPROVEMENT

The information contained in this ICSI Health Care Guideline is intended primarily for health profes-sionals and the following expert audiences:

• physicians, nurses, and other health care professional and provider organizations;

• health plans, health systems, health care organizations, hospitals and integrated health care delivery systems;

• health care teaching institutions;

• health care information technology departments;

• medical specialty and professional societies;

• researchers;

• federal, state and local government health care policy makers and specialists; and

• employee benefit managers.

This ICSI Health Care Guideline should not be construed as medical advice or medical opinion related to any specific facts or circumstances. If you are not one of the expert audiences listed above you are urged to consult a health care professional regarding your own situation and any specific medical questions you may have. In addition, you should seek assistance from a health care professional in interpreting this ICSI Health Care Guideline and applying it in your individual case.

This ICSI Health Care Guideline is designed to assist clinicians by providing an analytical framework for the evaluation and treatment of patients, and is not intended either to replace a clinician's judgment or to establish a protocol for all patients with a particular condition. An ICSI Health Care Guideline rarely will establish the only approach to a problem.

Copies of this ICSI Health Care Guideline may be distributed by any organization to the organization's employees but, except as provided below, may not be distributed outside of the organization without the prior written consent of the Institute for Clinical Systems Improvement, Inc. If the organization is a legally constituted medical group, the ICSI Health Care Guideline may be used by the medical group in any of the following ways:

• copies may be provided to anyone involved in the medical group's process for developing and implementing clinical guidelines;

• the ICSI Health Care Guideline may be adopted or adapted for use within the medical group only, provided that ICSI receives appropriate attribution on all written or electronic documents; and

• copies may be provided to patients and the clinicians who manage their care, if the ICSI Health Care Guideline is incorporated into the medical group's clinical guideline program.

All other copyright rights in this ICSI Health Care Guideline are reserved by the Institute for Clinical Systems Improvement. The Institute for Clinical Systems Improvement assumes no liability for any adaptations or revisions or modifications made to this ICSI Health Care Guideline.

Health Care Guideline:

Diagnosis and Management of Type 2 Diabetes Mellitus in AdultsI ICS

I NSTITUTE FOR C LINICAL S YSTEMS I MPROVEMENT A = Annotation

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Copyright © 2009 by Institute for Clinical Systems Improvement 1

Should patient be hospitalized?

6

A

Treatment goals for patients without cardiovascular disease:• Consider statin, unless contraindicated• LDL < 100 mg/dL• Blood pressure control (BP < 130/80)• Aspirin/antiplatelet medication optional• Smoking status: tobacco cessation if indicated

Recommend education andself-management:• Nutrition therapy• Physical activity• Weight management• Education for self-management• Foot care• Community resources

10

A

See Ongoing Management

algorithm

yes

no

Initial stabilization for outpatients requiring

immediate insulintreatment

9

A

Treatment goals not met:• Modify treatment based on appropriate related guideline• See Glycemic Control and Blood Pressure Control algorithms and/or• Consider referral to diabetes health team or specialists• Assess patient adherence• Evaluate for depression

16

Diagnostic testing for diabetes

1

A

Inpatient diabetes management

yes

Does patientneed outpatient

stabilization?

8

Are treatment goals met?

15

A

yes

17

A

Evaluation of patients with

elevated glucose

2

A

Diagnosis of type 2 diabetes

Diagnosis of prediabetes

Treatment to prevent or delay the progression to

diabetes

534

A A A

7

A

no

no

A

Complex patient factors to consider:• Known cardiovascular disease or high cardiovascular risk• Inability to recognize and treat hypoglycemia; history of severe hypoglycemia requiring assistance• Inability to comply with standard goals, such as polypharmacy issues• Limited life expectancy or estimated survival of less than 10 years• Cognitive impairment• Extensive comorbid conditions

11a

Set personalized A1c goal = A1c < 7% or individualize

to a goal < 8% based on factors in 11a

11

A

Treatment goals for patients with cardiovascular disease:• Consider statin, unless contraindicated• LDL < 70 mg/dL• Blood pressure control (BP < 130/80)• Aspirin/antiplatelet medication• Smoking status: tobacco cessation if indicated

14

A

A

no yes

Does patient have known cardiovascular

disease?

12

13

Thirteenth EditionMay 2009

Institute for Clinical Systems Improvement

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Glycemic Control Algorithm

Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Thirteenth Edition/May 2009

A = Annotation

Glycemic Control algorithm

18

A

Pharmacologic agent(s) – which is

best?

19

A

Prescribe insulin therapy

insulin See OngoingManagement algorithm

20

Prescribe non-insulin agents

• Titrate to goal

22

A

non-insulin

Glycemic control achieved?

23

See OngoingManagement algorithm

yes

Intensify therapy• Start insulin alone or insulin + other agent(s)

no

25

A

A

21

24


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Blood Pressure Control Algorithm


A = Annotation

Blood Pressure Control algorithm

26

A

Is systolic blood pressure

> 130 mmHg?

27

A

Treat systolic blood pressure to< 130 mmHg. While ACE inhibitors

and ARBs are preferred first-line therapy, two or more agents (to

include thiazide diuretics) may be required

28

A

yes

Is diastolic blood pressure

< 80 mmHg?

29

A

no

Treat diastolic blood pressure to < 80 mmHg

no

A

31

See Ongoing Management algorithm

yes

See Ongoing Management algorithm

30

32


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Ongoing Management Algorithm


A = Annotation

Ongoing management and follow-up of people with

diabetes

33

A

Maintain treatment goals: • Nutrition • Exercise • Monitor A1c every 3-6 months - Review blood glucose at each visit - Ask about hypoglycemia • Monitor lipid profile yearly • Monitor BP each visit • Ask about aspirin use • Ask about alcohol and tobacco use

34

A

Annual assessment of complications: • Targeted annual history and physical exam • Specialist dilated eye exam • Renal assessment • Comprehensive foot exam with risk assessment • Cardiovascular and cerebrovascular complication assessment • Special considerations

35

A

Treatment and referral for complications: • Nephropathy • Neuropathy • Retinopathy • Cardiovascular and cerebrovascular disease • Peripheral vascular disease

36

A

Are goals continuing to be

met?

37

no

yes

Treatment goals not met: • Modify treatment based on appropriate guidelines and/or • See Glycemic Control and Blood Pressure Control algorithms, and/or • Consider referral to diabetes health team or specialists • Assess patient adherence • Evaluate for depression

38


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Table of Contents


Work Group LeadersBruce Redmon, MDDivision of EndocrinologyUniversity of MinnesotaJoAnn Sperl-Hillen, MD Internal Medicine, HealthPartners Medical GroupWork Group MembersEndocrinologyRichard Bergenstal, MDPark NicolletSteve Smith, MDMayo ClinicFamily MedicineGreg Frane, MDNorthwest Family PhysiciansPatrick O'Connor, MDHealthPartners Medical GroupTodd Wade, MDMayo ClinicHealth EducationJulie Roberts, MS, RD, CDE HealthPartners Medical GroupInternal MedicineEugene Ollila, MDAllina Medical ClinicNursingPenny Louise Flavin, APRNOlmsted Medical CenterCarol Manchester, MSN, APRNFairview Health ServicesPharmacySarah Merbach, BS, RPhOlmsted Medical CenterVyvy Vo, PharmDHealthPartners Medical GroupFacilitatorMelissa Marshall, MBAICSI

Algorithms and Annotations ....................................................................................... 1-57Algorithm (Main) ................................................................................................................1Algorithm (Glycemic Control) ........................................................................................... 2Algorithm (Blood Pressure Control) .................................................................................. 3Algorithm (Ongoing Management) .................................................................................... 4Foreword

Scope and Target Population ......................................................................................... 6Clinical Highlights and Recommendations .................................................................. 6Priority Aims .............................................................................................................. 6-7Key Implementation Recommendations .................................................................... 7-8Related ICSI Scientific Documents .............................................................................. 8Disclosure of Potential Conflict of Interest ................................................................... 9Introduction to ICSI Document Development .............................................................. 9Description of Evidence Grading................................................................................ 10

Definitions .........................................................................................................................11Annotations ................................................................................................................. 12-55

Annotations (Main) ................................................................................................ 12-34Annotations (Glycemic Control)............................................................................ 34-47Annotations (Blood Pressure Control) ................................................................... 47-49Annotations (Ongoing Management) .................................................................... 49-55

Appendices .................................................................................................................. 56-57Appendix A – Treatment of Diabetic Nephropathy .....................................................56Appendix B – Using a Semmes-Weinstein Monofilament to Screen the Diabetic Foot for Peripheral Sensory Neuropathy ..................................................57

Supporting Evidence.................................................................................................. 58-101Brief Description of Evidence Grading ............................................................................ 59References ...................................................................................................................60-69Conclusion Grading Worksheets ...............................................................................70-101

Conclusion Grading Worksheet A – Annotation #4 (Prediabetes) ......................... 70-78Conclusion Grading Worksheet B – Annotation #11 (A1c) ................................... 79-85Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use) ................. 86-92Conclusion Grading Worksheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)......................................................................................93Conclusion Grading Worksheet E – Annotations #13, 14 (Aspirin Use) ............... 94-99Conclusion Grading Worksheet F – Annotations #28, 36 (Treatment with ACE Inhibitors or ARBs) ...........................................................100Conclusion Grading Worksheet G – Annotations #28, 36 (Thiazide Diuretics) ..............................................................................................101

Support for Implementation ................................................................................. 102-114Priority Aims and Suggested Measures ................................................................... 103-105Key Implementation Recommendations ................................................................. 106-107Knowledge Resources .................................................................................................... 107Resources Available................................................................................................. 108-114


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Foreword

Scope and Target PopulationTo provide a comprehensive approach to the diagnosis and management of prediabetes and type 2 diabetes mellitus in adults age 18 and older. Management will include nutrition therapy, physical activity, self-man-agement strategies, and pharmacologic therapy recommendations, as well as the prevention and diagnosis of diabetes-associated complications and risk factors.

The diagnosis of gestational diabetes or the management of diabetes in patients who are pregnant is excluded from the scope of this guideline. Oral agents do not have Food and Drug Administration approval for use in pregnancy. The glucose goals are different in pregnancy and require more aggressive treatment.

Please refer to the ICSI Routine Prenatal guideline for information relating to gestational diabetes.

The diagnosis and management of type 1 diabetes is not included in this guideline.

Clinical Highlights and Recommendations• Education and self-management support is necessary for people with diabetes to manage their disease.

(Annotation #10)

• Focus on cardiovascular risk reduction (blood pressure control, low-density lipoprotein cholesterol control and statin use, aspirin use and tobacco cessation). (Annotations #11, 13, 14)

• A1c levels should be individualized to the patient. (Annotation #11)

• Aggressive blood pressure control is just as important as glycemic control. Systolic blood pressure level should be the major factor for detection, evaluation and treatment of hypertension. The use of two or more blood pressure lowering agents is often required to meet blood pressure goal. (Annotations #13, 14)

• Prevent microvascular complications through annual or biannual eye exams, foot risk assessments and foot care counseling, and annual screening for proteinuria. (Annotation #35)

• Initial therapy with lifestyle treatment and metformin is advised unless contraindicated. (Annotations #4, 10)

Priority AimsA multifactorial intervention targeting hyperglycemia and cardiovascular risk factors in individuals with diabetes is most effective. Both individual measures of diabetes care as well as comprehensive measures of performance on broader sets of measures are recommended. A randomized controlled trial has shown a 50% reduction in major cardiovascular events through a multifactorial intervention targeting hypergly-cemia, hypertension, dyslipidemia, microalbuminuria, aspirin and ACE inhibitor use in individuals with microalbuminuria (Gaede, 2003 [A]).

Goals for A1c, low-density lipoprotein, and other diabetes measures should be personalized, and lower goals for A1c and low-density lipoprotein than those included here in the priority aims and measures may be clinically justified in some adults with type 2 diabetes. However, efforts to achieve lower A1c below 7% may increase risk of mortality, weight gain, hypoglycemia and other adverse effects in many patients with type 2 diabetes. Therefore, the aims and measures listed here are selected carefully in the interests of patient safety.



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1. Diabetes Optimal Care Measures: Maximize the percentage of adult patients, ages 18-75 with type 2 diabetes mellitus, who in a defined period of time achieve any of the possible measures of established control.

2. Diabetes Optimal Care Comprehensive Measure Set: Maximize the percentage of adult patients ages 18-75 with type 2 diabetes mellitus, who in a one-year period of time achieved the identified measures of care.

3. Diabetes Process of Care Measure Set: Maximize the percentage of adult patients ages 18-75 with type 2 diabetes mellitus for whom recommended screening procedures are done.

4. High-Risk Population Measures: The purpose of this aim is to identify and focus on a higher risk population by decreasing the percentage of adult patients, ages 18-75 with type 2 diabetes mellitus, with poorly controlled glucose and cardiovascular risk factors (clinical strategies that target high-risk populations may be more viable with limited resources).

Key Implementation RecommendationsThe implementation of type 2 diabetes mellitus clinical guidelines at medical groups and clinics is a complex and challenging task. However, a number of key processes have been shown to accelerate effective clinical guideline implementation and care improvement (Sperl-Hillen, 2005 [D]). These overlapping care elements can be categorized at the medical group and provider levels:

• Essential Elements at the Medical Group Level:

- Leadership. Medical group leaders must communicate the need for change in clinical practice patterns and consistently identify improvement priorities.

- Resources. Resources adequate to the task at hand will be needed to assure the success of a change effort. Resources may include staff time, money and provision of tools (such as elec-tronic medical records) to support care improvement.

- Select Specific Improvement Goals and Measures. For most chronic diseases, including diabetes, the most efficient improvement strategy is to focus on a limited number of specific improvement goals. These may be based on observed gaps in care, potential clinical impact, cost considerations or other criteria (O'Connor, 2005a [R]). In type 2 diabetes, focusing on glycemic control, lipid control and blood pressure control is a strategy that has been shown to be effective in preventing up to 53% of heart attacks and strokes, the leading drivers of excess mortality and costs in adults with diabetes (Gaede, 2003 [A]).

- Accountability. Accountability within the medical group is a management responsibility, but external accountability may also play an important enhancing role to motivate sustained efforts to implement guidelines and improve care. Examples of external accountability include participation in shared learning activities (such as Institute for Healthcare Improvement or ICSI and its Action Groups), or public reporting of results (such as in pay-for-performance or the Minnesota Community Measures Project).

- Prepared Practiced Teams. The medical group may need to foster the development of prepared practice teams that are designed to meet the many challenges of delivering high-quality chronic disease care.

• Essential Elements at the Clinic Level:

- Develop "Smart" Patient Registries. These are registries that are designed to identify, automatically monitor, and prioritize patients with diabetes based on their risk, current level of control, and possibly patient readiness-to-change.

Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Foreword Thirteenth Edition/May 2009


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- Assure "Value-Added" Visits. These are office visits or other patient encounters (by phone, e-mail, etc.) that include intensification of treatment if the patient has not yet reached his/her evidence-based clinical goals. Failure of providers and patients to intensify treatment when indicated (referred to as "clinical inertia") is a key obstacle to better diabetes care (O'Connor, 2003 [R]; O'Connor, 2005a [R]; O'Connor, 2005b [R]). HSR editorial. Previsit planning and best practice prompts may help to increase the efficiency of patient visits and remind providers of needed tests and care.

- Develop "Active Outreach." These are strategies to reach patients with chronic disease who have not returned for follow-up or for other selected elements of care. Outreach strategies that enhance the likeliness of a future provider encounter that addresses one of the barriers to patient activation (discussed below) may be more effective. Simple reporting of lab test results or care suggestions through the mail may be ineffective at addressing these barriers.

- Emphasize "Patient Activation" Strategies. These may include diabetes education and other actions designed to sustain engagement of patients with their diabetes care. Many patients with diabetes either (a) do not really believe they have diabetes, or (b) do not really believe that diabetes is a serious disease, or (c) lack motivation for behavioral change, or (d) do not believe that recommended treatments will make a difference to their own outcomes. For care to be effective, these issues must be addressed for many patients (O'Connor, 1997 [D]).

Related ICSI Scientific DocumentsGuidelines

• Hypertension Diagnosis and Treatment

• Lipid Management in Adults

• Major Depression in Adults in Primary Care

• Preventive Services for Adults

• Prevention and Management of Obesity (Mature Adolescents and Adults)

• Primary Prevention of Chronic Disease Risk Factors

• Stable Coronary Artery Disease

Order Sets

• Subcutaneous Insulin Management Order Set



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Disclosure of Potential Conflict of InterestICSI has adopted a policy of transparency, disclosing potential conflict and competing interests of all indi-viduals who participate in the development, revision and approval of ICSI documents (guidelines, order sets and protocols). This applies to all work groups (guidelines, order sets and protocols) and committees (Committee on Evidence-Based Practice, Cardiovascular Steering Committee, Women's Health Steering Committee, Preventive & Health Maintenance Steering Committee and Respiratory Steering Committee).

Participants must disclose any potential conflict and competing interests they or their dependents (spouse, dependent children, or others claimed as dependents) may have with any organization with commercial, proprietary, or political interests relevant to the topics covered by ICSI documents. Such disclosures will be shared with all individuals who prepare, review and approve ICSI documents.

Richard Bergenstal, MD has stock in Merck through a family inheritance. Dr. Bergenstal participates in clinical research and/or serves on a scientific advisory board for Amylin, Merck, Pfizer, ResMed, Valeritas, Eli Lilly, Novo Nordisk, Sanofi-Aventis, MannKind, Intuity, Roche, LifeScan, Abbott, Bayer and Medtronic. All compensation goes directly to the non-profit Park Nicollet Institute. Dr. Bergenstal is an officer within the American Diabetes Association.

Carol Manchester, MSN, APRN received speakers' fees or honorarium from Sanofi-Aventis and Pfizer.

Patrick O'Connor, MD receives research or grant funding from HealthPartners Research Foundation; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute for Health; National Heart, Lung, and Blood Institute; Robert Wood Johnson Foundation, Agency for Healthcare Research and Quality; Centers for Disease Control; Minnesota Department of Health, University of Minnesota. Dr. O'Connor received speakers' fees or honorarium from Merck.

Bruce Redmon, MD is contracted with Ingenix and receives research or grant funds from Mannkind Corp.

Steve Smith, MD is a member of the national board of directors for the American Diabetes Association.

JoAnn Sperl-Hillen, MD receives research support from National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; and Merck.

No other work group members have potential conflicts of interest to disclose.

Introduction to ICSI Document DevelopmentThis document was developed and/or revised by a multidisciplinary work group utilizing a defined process for literature search and review, document development and revision as well as obtaining input from and responding to ICSI members.

For a description of ICSI's development and revision process, please see the Development and Revision Process for Guidelines, Order Sets and Protocols at http://www.icsi.org.



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Evidence Grading SystemA. Primary Reports of New Data Collection:

Class A: Randomized, controlled trial

Class B: Cohort study

Class C: Non-randomized trial with concurrent or historical controls Case-control study Study of sensitivity and specificity of a diagnostic test Population-based descriptive study

Class D: Cross-sectional study Case series Case report

B. Reports that Synthesize or Reflect upon Collections of Primary Reports:

Class M: Meta-analysis Systematic review Decision analysis Cost-effectiveness analysis

Class R: Consensus statement Consensus report Narrative review

Class X: Medical opinion

Citations are listed in the guideline utilizing the format of (Author, YYYY [report class]). A full explanation of ICSI's Evidence Grading System can be found at http://www.icsi.org.



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DefinitionsPrediabetes: Hyperglycemia not sufficient to meet the diagnostic criteria for diabetes. Formerly catego-rized as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), depending on whether it is identified through a fasting plasma glucose test or oral glucose tolerance test. Diagnosis of prediabetes is based on:

• Fasting plasma glucose of 100 mg/dL to 125 mg/dL

• Oral glucose tolerance test – two-hour plasma glucose of 140 mg/dL to 199 mg/dL

Type 2 Diabetes Mellitus: Diabetes that results from a progressive insulin secretory defect on the back-ground of insulin resistance. The diagnosis of type 2 diabetes is based on:

• Symptoms of diabetes and a casual plasma glucose of greater than or equal to 200 mg/dL

- Casual is defined as any time of day without regard to time since last meal.

- The classic symptoms of diabetes include polyuria, polydipsia and unexplained weight loss, excessive hunger, fatigue or wounds that are slow to heal or frequent skin infections.

• Fasting plasma glucose of greater than or equal to 126 mg/dL on two occasions

- Fasting is defined as no caloric intake for at least eight hours.

• Oral glucose tolerance test – two-hour plasma glucose of 200 mg/dL

- The oral glucose tolerance test should be performed as described by the World Health Organi-zation, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water.

- Verified by repeat test on a separate occasion.

(American Diabetes Association, 2007a [R])



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Algorithm Annotations

1. Diagnostic Testing for DiabetesPrediabetes is now the term recommended for patients with impaired glucose tolerance or impaired fasting glucose. Type 2 diabetes is frequently not diagnosed until complications appear, and approximately one-third of all people with diabetes may be undiagnosed (American Diabetes Association, 2007c [R]).

Possible tests to assess for diabetes include a fasting plasma glucose or an oral glucose tolerance test. A fasting blood glucose is the preferred test for screening for diabetes (American Diabetes Association, 2007c [R]).

Patients presenting with symptoms of diabetes should be tested.

Risk factors for diabetes include:

• Risk factors for athrosclerosis: smoking, hypertension, dyslipidemia.

• Age, race/ethnicity, family history of diabetes, prior history of diabetes, physical inactivity, cardio-vascular disease, cerebral vascular disease, hyperlipidemia, overweight/obese (as defined by body mass index), low high-density lipoprotein, high triglycerides, polycystic ovarian syndrome.

• Gestation history of an infant weighing more than nine pounds, toxemia, stillbirth or previous diagnosis of gestational diabetes.

Testing patients with hypertension, blood pressure over 130/80, dyslipidemia or heart disease are also recommended.

See the ICSI Hypertension Diagnosis and Treatment guideline, the ICSI Lipid Management in Adults guideline, the ICSI Preventive Services in Adults guideline, the Prevention and Management of Obesity (Mature Adolescents and Adults) guideline, and the Stable Coronary Artery Disease guideline for more information.

2. Evaluation of Patients with Elevated GlucoseEvaluation may be completed in one or more visits over a reasonably short period of time. Clinical judg-ment is needed to determine the urgency of completing the evaluation.

History (American Diabetes Association, 2007c [R])

• Symptoms

• Eating habits, weight history

• Physical activity

• Prior or current infections, particularly skin, foot, dental and genitourinary

• Symptoms and treatment of chronic complications associated with diabetes: eye, heart, kidney, nerve, genitourinary (including sexual function), peripheral vascular and cerebrovascular (these may be present at diagnosis)

• Current medications including over-the-counter medications, dietary supplements and alternative therapies with a focus on medications known to induce diabetes-type states (e.g., steroids, atypical antipsychotics)



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• Psychosocial, cultural and economic factors that might influence the management of diabetes

• Alcohol/drug use

Physical examination (American Diabetes Association, 2007c [R])

• Weight, height, body mass index (BMI), blood pressure

• Cardiovascular system: heart, blood pressure, peripheral vascular including pulses and bruits (abdominal, carotid, femoral)

• Feet: nails, web spaces, ulcers, pulses, calluses, structural deformities, protective sensation and shoes

• Other examinations as guided by the patient's symptoms and/or concerns:

- Skin: infections or diseases such as acanthosis nigricans, xanthomia

- Neurological symptoms: sensory state of hands and feet, muscle wasting, deep tendon reflexes

- Mental health: screen for depression and/or anxiety

- Referral to an eye specialist to assess optic health

- Referral to a dentist to assess oral health

Laboratory evaluation

• Fasting plasma glucose or random plasma glucose

• A1c (not required for prediabetes)

• Fasting lipid profile: total cholesterol, high-density lipoprotein (HDL cholesterol), low-density lipoprotein (LDL cholesterol) and triglycerides

• Serum creatinine and liver function test alanine aminotransferase (ALT) or aspartate aminotrans-ferase (AST)

• Urine: ketones, glucose, protein, microalbuminuria, and culture if microscopic is abnormal or symptoms of infection present

Urine microalbumin tests can identify patients with early diabetic nephropathy when intervention may be most effective in delaying or preventing end-stage renal disease. Single tests for urinary microalbumin and urinary creatinine can accurately detect urinary microalbumin excretion.

For more information, see Annotation #35, "Annual Assessment of Complications" (American Diabetes Association, 2004d [R]; Nelson, 1991 [B]).

Increased urinary microalbumin is a predictor of increased cardiovascular mortality (American Diabetes Association, 2007c [R]).

3. Diagnosis of Prediabetes• Fasting plasma glucose of 100 mg/dL to 125 mg/dL

• Oral glucose tolerance test two-hour plasma glucose: 140 mg/dL to 199 mg/dL

(American Diabetes Association, 2007c [R])

Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Algorithm Annotations Thirteenth Edition/May 2009


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4. Treatment to Prevent or Delay the Progression to DiabetesPatients who are identified with prediabetes should be referred for education and lifestyle interventions. Health care providers should follow up with patients diagnosed with prediabetes on an annual basis to monitor their progress and review treatment goals (American Diabetes Association, 2007c [R]).

Intensive lifestyle change or programs have been proven effective in delaying or preventing the onset of diabetes by about 50%. Effective lifestyle changes include setting achievable goals, obtaining weight loss when needed (ideally at least 5% total body weight), and increasing physical activity (Tuomilehto, 2001 [A]).

• Lifestyle modifications, such as nutrition, exercise and even modest weight loss, are recommended for prevention or delayed progression of patients with prediabetes.

• Pharmacotherapy, such as metformin, are effective in some patients with prediabetes.

• There are concerns that the recent modification of the definition of impaired fasting glucose by the American Diabetes Association has low specificity and low positive predictive value compared to the WHO definition.

[Conclusion Grade II: See Conclusion Grading Worksheet A – Annotation #4 (Prediabetes)]

The following initial approaches are recommended for people with prediabetes:

• Intensive lifestyle behavioral change including a nutrition and activity plan by a registered dietitian, health educator or other qualified health professional. Ongoing support of behavioral change is necessary.

• Cardiovascular risk reduction appropriate to the needs of the individual

Patients who respond to lifestyle interventions:

• Annual follow-up and reassessment of risks for developing diabetes (American Diabetes Associa-tion, 2004g [R]; Chiasson, 2002 [A]; Eriksson, 1999 [R]; Heart Outcomes Prevention Evaluation Study Investigators, 2002 [A]; Kelley, 2002 [A]; Miles, 2002 [A])

Patients who are high risk and not responding to lifestyle interventions:

• Intensify education and counseling on lifestyle interventions.

• There is some evidence of prevention of diabetes through pharmacotherapy with biguanides and alpha glycosidase inhibitors (Diabetes Prevention Program Research Group, 2002 [A]; Gillies, 2007 [M]). Rosiglitazone has been shown to prevent diabetes, but the risk of congestive heart failure was increased (DREAM Trial Investigators, 2006 [A]). Lifestyle change remains the preferred method to prevent diabetes (Diabetes Prevention Program Research Group, 2002 [A]; Gillies, 2007 [M]).

5. Diagnosis of Type 2 DiabetesDiagnosis of type 2 diabetes (American Diabetes Association, 2007a [R]):

• Fasting plasma glucose greater than or equal to 126 mg/dL on two separate occasions.

• Casual plasma glucose greater than or equal to 200 mg/dL plus typical symptoms of diabetes.

• In the absence of unequivocal hyperglycemia associated with acute metabolic decompensation, the results should be confirmed by repeat testing on a different day.

• At the present time A1c should not be used to diagnose diabetes.



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History

• Details of previous treatment programs, including diabetes education

• Current treatment of diabetes, including medications, nutrition, physical activity patterns and results of glucose monitoring

• Frequency, severity and cause of acute complications such as hypoglycemia, hyperglycemia and non-ketotic hyperosmolar coma

6. Should Patient Be Hospitalized?Inpatient care may be appropriate in the following situations (American Diabetes Association, 2004d [R]):

• Elderly patients with infection or illness, weight loss, dehydration, polyuria or polydipsia

• Life-threatening acute metabolic complications of diabetes:

- Hyperglycemic hyperosmolar state with impaired mental status, elevated plasma osmolaity that includes plasma glucose greater than 600 mg/dL

- Diabetic ketoacidosis with a plasma glucose greater than 250 mg/dL, arterial pH less than 7.30 and serum bicarbonate level less than 15 mEq/L and the presence of moderate ketonuria and/or ketonemia

- Hypoglycemia with neuroglycopenia that includes blood glucose less than 50 mg/dL and treat-ment has not resulted in prompt recovery, coma, seizures or altered behavior

• Uncontrolled insulin-requiring diabetes during pregnancy

• Surgery, infection, steroids – if these conditions cause significant hyperglycemia and rapid initiation of rigorous insulin is needed

7. Inpatient Diabetes ManagementHospitalized inpatients with diabetes suffer increased morbidity, mortality, length of stay, and other related hospital costs compared to non-hyperglycemic inpatients. These negative outcomes are observed more frequently in hospitalized patients with newly discovered hyperglycemia. Hyperglycemia is an independent marker of inpatient mortality in patients with undiagnosed diabetes (Umpierrez, 2002 [B]).

Hyperglycemia has been associated with increased infection rates and poorer short-term and long-term outcomes in critically ill patients in the intensive care unit, post-myocardial infarction, and post-surgical settings. Studies support that aggressive glucose management in medical and surgical patients can improve outcomes (van den Berghe, 2001 [A]).

The following are recommended in the inpatient setting (Clement, 2004 [R]):

• Intensive insulin therapy with intravenous insulin in critically ill patients (van den Berghe, 2001 [R])

• Use of scheduled insulin, with basal coverage (improves glucose control compared to sliding scale coverage alone)

• For insulin-deficient patients, despite reductions or the absence of caloric intake, basal insulin must be provided to prevent diabetic ketoacidosis



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• Target preprandial plasma glucose levels are 90-130 mg/dL (American Diabetes Association, 2004b [R]; Clement, 2004 [R]; Garber, 2004 [R])

• If measured, the target postprandial plasma glucose is less than 180 mg/dL (American Diabetes Association, 2004b [R]; Clement, 2004 [R]; Garber, 2004 [R])

• Establishing a multidisciplinary team that sets and implements institutional guidelines, protocols and standardized order sets for the hospital results in reduced hypoglycemic and hyperglycemic events

Other considerations include (Clement, 2004 [R]):

• For patients who are alert and demonstrate accurate insulin self-administration and glucose moni-toring, insulin self-management should be allowed as an adjunct to standard nurse-delivered diabetes management.

• Patients with no prior history of diabetes who are found to have hyperglycemia (random fasting blood glucose greater than 125 mg/dL or random glucose of 200 mg/dL or more) during hospitaliza-tion should have follow-up testing for diabetes within one month of hospital discharge (Umpierrz, 2002 [B]).

Please see ICSI's Subcutaneous Insulin Management order set for additional information regarding inpatient glucose management.

8. Does Patient Need Outpatient Stabilization?Indications for immediate insulin treatment in type 2 diabetes mellitus (Clements, 1987 [A]; Nathan, 2006 [R])

• Severe symptoms, marked weight loss, polyuria, polydypsia

- Fasting plasma glucose greater than 300 mg/dL fasting, or

- Random glucose over 350 mg/dL, or

- A1c over 10%, or

- Presence of ketonuria

Insulin therapy may not be permanent once patient is stabilized.

9. Initial Stabilization for Outpatients Requiring Immediate Insulin TreatmentIf the patient presents and is considered stable enough for outpatient care but meets indications noted above for starting insulin, the work group offers several acceptable ways of initiating insulin:

• One example is to calculate the total daily dose of insulin at 0.3 units/kg and start bedtime glargine at 50% of the total dose, splitting the remaining 50% with short-acting insulin before meals.

• Another example is to start an oral agent while simultaneously initiating glargine at a dose of approximately 0.1 units/kg.

• A third example is to calculate the total daily dose of insulin at 0.3 units/kg and use premixed insulin with 2/3 the dose in the a.m. and 1/3 in the p.m.

At presentation, all patients should be instructed on glucose monitoring, hypoglycemia recognition and treatment, and how/when to contact health care support. Patients should check glucose frequently when



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insulin is initiated. Patients should receive daily phone or visit contact for at least three days and have 24-hour emergency phone support if needed.

Patients should be referred for nutrition and diabetes education and be seen in a timely way after diagnosis, e.g., within one to seven days.

Insulin therapy may not be permanent, particularly if oral agents are added or if, at presentation, the patient is in metabolic stress such as infections, acute metabolic complications, recent surgery (Peters, 1996 [D]). As the metabolic stress resolves, the insulin dose requirements may rapidly fall.

For the occasional unstable patient with type 2 diabetes, maximal doses of oral hypoglycemic agents may afford an approach to the patient who is psychologically resistant to or refuses insulin initiation.

10. Recommend Education and Self-ManagementNutrition TherapyMedical nutrition therapy for diabetes emphasizes improving metabolic outcomes by modifying nutrient intake and lifestyle. Major goals are to attain and maintain in the normal or as close to normal range as is safely possible glucose, blood pressure and lipid/lipoprotein levels. These prevent or slow the development of the chronic complications of diabetes (American Diabetes Association, 2008 [R]).

The priority for nutrition therapy for type 2 diabetes is to implement lifestyle strategies that will reduce hyperglycemia and hypertension and improve dyslipidemias (American Dietetic Association, 2008 [R]; American Diabetes Association, 2008 [R]). Because many individuals are insulin resistant and overweight or obese, nutrition therapy often begins with strategies that reduce energy intake and increase energy expen-diture through physical activity. Many individuals may have already tried unsuccessfully to lose weight and it is important to note that lifestyle strategies, independent of weight loss, can improve glucose control and risk factors for cardiovascular disease.

Moderate weight loss (5% of body weight) is associated with decreased insulin resistance, improved measures of glycemic and lipidemia, and reduced blood pressure. The optimal macronutrient distribution of weight loss diets has not been established (American Diabetes Association, 2008 [R]).

Low carbohydrate diets, restricting total carbohydrate to less than 130 g/day, are not recommended in the management of diabetes.

Appropriate nutrition therapy will be developed collaboratively with the person who has diabetes. Instruc-tion may require a provider with expertise in medical nutrition therapy, and instruction may be obtained through individual or group consultation (Franz, 1995a [A]). It is important that physicians understand the general principles of medical nutrition therapy and support them for patients with diabetes. In most people, nutrition recommendations are similar to those of the general population. Medical nutrition therapy is a Medicare Part B-covered benefit.

• Evaluate the patient's current eating habits and modify as needed. Recommend:

- Working together toward gradual, realistic and culturally appropriate lifestyle change goals.

- Maintaining the pleasure of eating by limiting only food choices indicated by scientific evidence.

- Healthful food choices: foods containing carbohydrates from whole grains, fruits, vegetables, legumes and low-fat milk should be included in a healthy eating plan.

- Reducing total caloric intake by moderating food/beverage and limiting total fat intake.

- Distributing carbohydrates evenly throughout the day to smaller meals and snacks.



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- Monitoring carbohydrates remains a key strategy in achieving glycemic control, whether by carbo-hydrate counting, exchanges or experience-based estimation (American Diabetes Association, 2008 [R]).

- If one chooses to drink alcohol and has not been cautioned against it, limit intake to one drink per day for women and two drinks per day for men, according to USDA guidelines. A drink is defined as 12 oz. of regular beer, 5 oz. of wine, or 1.5 oz. of 80-proof distilled spirits. To reduce the risk of hypoglycemia, alcohol should be consumed with food.

• Individualize the nutrition prescription based on the nutrition assessment and treatment goals of each patient. For example, if the patient has been eating 45% of calories from fat, lowering fat to even 40% can be helpful.

Carbohydrate (American Diabetes Association, 2009 [R])

• Both the quantity and the type or source of carbohydrate in food influences post-prandial glucose levels.

• For individuals with diabetes, the use of glycemic index and glycemic load may provide a modest additional benefit for glycemic control over that observed when total carbohydrate is considered alone.

• Sucrose (e.g., table sugar) and sucrose-containing foods do not need to be restricted. However, they should be substituted for other carbohydrate sources, or if added, covered with insulin or other glucose-lowering medication. They should be eaten within the context of a healthy diet and avoid excess energy intake.

• Added fructose as a sweetening agent is not recommended as it may adversely affect plasma lipids. Naturally occurring fructose in fruits, vegetables and other foods does not need to be avoided.

• The use of sugar alcohols, such as sorbitol or manitol in small amounts, appears to be safe; however, they may cause gastrointestinal side effects. When calculating carbohydrate content of foods containing sugar alcohols, subtract half of sugar alcohol grams from total carbohydrate grams (American Diabetes Association, 2008 [R]).

• Sugar alcohols and non-nutritive sweeteners are safe when consumed within the acceptable daily intake levels established by the Food and Drug Administration.

• Encourage consuming a wide variety of fiber-containing foods such as legumes, fiber-rich cereals, fruits, vegetables and whole grain products to achieve fiber intake goals of 14 g/1,000 calories.

Protein (American Diabetes Association, 2007b [R]; American Diabetes Association, 2008 [R])

• 15%-20% of the total calories. Avoid protein intakes of greater than 20% of total daily energy. The long-term effects of consuming more than 20% of energy as protein on the development of nephropathy have not been determined. High-protein diets are not recommended as a method of weight loss at this time.

• Reduction of protein intake to 0.8-1 gm/kg in individuals with diabetes in the earlier stages of chronic kidney disease and to 0.8 gm/kg in the later stages of chronic kidney disease is recommended and may improve measures of renal function (urine albumin excretion rate, glomerular filtration rate).

• Protein does not increase plasma glucose concentrations but does increase serum insulin responses, and thus protein should not be used to treat acute or prevent nighttime hypoglycemia.



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Fat (American Diabetes Association, 2007b [R]; American Diabetes Association, 2008 [R])

• Patients with normal weight and lipids: continue maintaining healthy weight and lipids that include less than or equal to 30% calories from fat, less than 7% saturated fats, limit of trans fats, and less than 200 mg cholesterol (Klein, 2004 [R]).

• Weight control: balance lower fat and caloric consumption with regular physical activity of 30 minutes most days.

• Patients with elevated cholesterol and low-density lipoprotein cholesterol: implement National Cholesterol Education Program-Therapeutic Lifestyle recommendations. Program-Therapeutic Lifestyle diet: reduce saturated fat to less than 7% calories and cholesterol to less than 200 mg, consider increased soluble fiber intake (10-25 g/day) and plant stanols/sterols (2 g/day), and mini-mize trans fat intake.

• Two or more servings of fish per week (with the exception of commercially fried fish fillets) provide omega-3 fatty acids and are recommended.

• Patients with elevated triglycerides: improve glucose control, encourage weight loss, increase physical activity, moderate carbohydrate intake and limit dietary saturated fat and trans fat. Increase consumption of omega-3 fatty acids from fish or supplements, which has been shown to reduce adverse cardiovascular outcomes (Wang, 2006 [M]).

Sodium (American Diabetes Association, 2007b [R])

• Medical nutrition therapy for hypertension control focuses on weight reduction and recommended sodium intakes of 2,300 mg/day for normotensive and hypertensive individuals and a sodium intake less than 2,000 mg/day for patients with diabetes and symptomatic heart failure. Additional recom-mendations include consuming five to nine servings of fruits and vegetables daily, and two to four daily servings of low-fat dairy products rich in calcium, magnesium and potassium.

Supplements (American Diabetes Association, 2009 [R])

• Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not advised because of lack of evidence of efficacy and concern related to long-term safety.

• Benefit from chromium supplementation in people with diabetes or obesity has not been conclusively demonstrated and, therefore, cannot be recommended.

Physical activity and behavior modification are important components of weight loss programs and are most helpful in maintenance of weight loss.

Structured programs that emphasize lifestyle changes including education, reduced energy and fat intake (approximately 30% of total energy), regular physical activity and frequent participant contact are neces-sary to produce long-term weight loss of 5%-7% of starting weight. Lifestyle change should be the primary approach to weight loss (American Diabetes Association, 2007b [R]).

When usual measures to promote weight loss are unsuccessful in severely obese individuals with comorbidi-ties, there may be a role for adjunctive pharmacotherapy or surgical procedures.

There is some evidence that pharmacotherapy for weight loss may offer short-term benefit for a subset of patients with type 2 diabetes (Hollander, 1998 [A]; Kelley, 2002 [A]; Miles, 2002 [A]). The studies, however, were of relatively weak design, and pharmacotherapy for weight loss cannot be recommended for most patients with type 2 diabetes.

Patients should be provided with ongoing nutrition self-management and care support (American Diabetes Association, 2007b [R]).



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Physical ActivityPeople with diabetes should peform at least 150 minutes a week of moderate intensity activity (50%-70% maximum heart rate), and strengthening exercises three times a week unless contraindicated.

The positive benefits of physical activity include improved blood pressure values, improved lipid profile, improved cardiac status, increased insulin sensitivity, more effective weight management and improved glycemic control, and it helps in the management of depressive symptoms. Because the positive effects of increased physical activity diminish within days of the cessation of exercise, regular activity is recom-mended (Bourn, 1994 [D]).

Recent studies indicate that cumulative daily physical activity may be almost as beneficial as continuous physical exertion (De Buske, 1990 [A]; Hardman, 1999 [R]). The major emphasis is to gradually increase level of physical activity either by increasing duration or frequency.

Epidemiological studies suggest that regular aerobic physical activity is beneficial for the treatment of type 2 diabetes mellitus (American Diabetes Association, 2004e [R]; Helmrich, 1991 [C]).

Reinforce the ongoing need and benefits of physical activity at each visit, offering support and advice on ways to incorporate 30 minutes of physical activity into most days of the week (Pate, 1995 [R]).

Results of self-monitoring glucose can be useful in preventing hypoglycemia and adjusting medications, medical nutrition therapy and physical activity.

Hypoglycemia is a risk in individuals who participate in physical activity and are taking insulin, sulfonylu-reas and/or meglitinides. Depending on the level of physical activity, the medication dosage or the amount of carbohydrate ingested, hypoglycemia can occur. For patients on these drug classes and pre-exercise glucose monitor results are less than 100 mg/dL, additional carbohydrate should be ingested for prevention of hypoglycemia (American Diabetes Association, 2008 [R]).

Strategies for initiation of increased physical activity

• Start by incorporating 10 minutes of increased activity into each day

- Use stairs instead of elevator.

- Park car away from building entrance and walk.

- Walk to do errands.

• Overcome barriers

- Self-monitor activity performed using pedometer, time record and/or journal.

- Be consistent.

- Have alternative activities for inclement weather.

- Find enjoyable activities.

- Be active at the time of day that is best for the individual.

- Doing a physical activity with a partner and/or being accountable to someone regarding your progress greatly improves the ability to be successful (American Diabetes Association, 2008 [R]).



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Medical evaluation to assess safety of exercise program

• Assess physical condition and limitations of the patient.

• Assess for cardiovascular disease. Atypical symptoms and painless ischemia are more common in patients with diabetes (Janard-Delenne, 1999 [D]).

• Cardiac stress testing: there is no evidence that stress testing is routinely necessary in asymptomatic people before beginning a moderate-intensity exercise program such as walking.

• Cardiac stress testing should be considered for the previously sedentary individual at moderate to high-risk for cardiovascular disease or other patients who are clinically indicated who want to undertake vigorous aerobic exercise that exceeds the demands of everyday living (American Diabetes Association, 2007c [R]).

• Assess glucose control.

• Assess knowledge of physical activity in relation to glucose control.

• When making a referral, make other health care providers aware of limitations for exercise.

Physical activity can be intermittent or cumulative (DeBuske, 1990 [A]; Hardman, 1999 [R]; Pate, 1995 [R].

Weight ManagementWhen usual measures to promote weight loss are unsuccessful in severely obese individuals with comorbidi-ties, there may be a role for adjunctive pharmacotherapy or surgical procedures.

There is some evidence that pharmacotherapy for weight loss may offer short-term benefit for a subset of patients with type 2 diabetes (Hollander, 1998 [A]; Kelley, 2002 [A]; Miles, 2002 [A]). The studies, however, were of relatively weak design, and pharmacotherapy for weight loss cannot be recommended for most patients with type 2 diabetes.

Bariatric surgery has recently been discussed as an option for some individuals with type 2 diabetes who have a body mass index of 35 kg/m2 or more. Bariatric surgery can result in marked improvements in glycemia; however, the long-term benefits and risks need to be studied further (American Diabetes Associa-tion, 2007b [R]).

Weight loss is also an important goal because it improves insulin resistance, glycemic control, blood pressure and lipid profiles. Moderate weight loss (5% of body weight) can improve fasting blood glucose in many overweight or obese persons (Pastors, 2002 [R]). Low-carbohydrate diets, restricting total carbohydrate to less than 130 g/day, are not recommended in the management of diabetes.

There is considerable interest in low-carbohydrate diets for weight loss; however, the long-term effects of these diets are unknown and although such diets produce short-term weight loss, maintenance of weight loss is similar to that of low-fat diets, and impact on cardiovascular disease risk profile is uncertain (American Diabetes Association, 2007b [R]).

Low-carbohydrate diets, restricting total carbohydrate to less than 130 g/day, are not recommended in the management of diabetes. For weight loss, either low-carbohydrate or low-fat calorie-restricted diets may be effective in the short-term (up to one year) (Standards of Medical Care in Diabetes, 2009 [R]).

Further research is needed to determine the long-term efficacy and safety of low-carbohydrate diets (Klein, 2004 [R]).



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A recent meta-analysis showed at six months, low-carbohydrate diets were associated; with greater improve-ments in triglyceride and high-density lipoprotein cholesterol than low-fat diets, however, low-density lipoprotein cholesterol was significantly higher in low-carbohydrate diets (Nordmann, 2006 [M]). For patients on low-carbohydrate diets, monitor lipid profiles, renal function and protein intake (in those with nephropathy), and adjust hypoglycemic therapy as needed (American Diabetes Association Standards of Medical Care in Diabetes, 2009 [R]).

Please see the Prevention and Management of Obesity (Mature Adolescents and Adults) guideline for more information.

Appropriate nutrition therapy will be developed collaboratively with the person who has diabetes. Instruc-tion may require a provider with expertise in medical nutrition therapy, and instruction may be obtained through individual or group consultation (Franz, 1995a [A]; Franz, 1995b [M]; Franz, 2002 [R]). It is important that physicians understand the general principles of medical nutrition therapy and support them for patients with diabetes. In most people, nutrition recommendations are similar to those of the general population. Medical nutrition therapy is a Medicare Part B-covered benefit.

Education for Self-ManagementAdequate self-management support for patients requires integration of available self-management educa-tion and support resources into routine care. Usually appropriate education may require the expertise of the diabetes educator. This instruction can be obtained through individual or group consultation (Franz, 1995a [A]; Franz, 1995b [M]; Franz, 2002 [R]). Medicare reimbursement for diabetes self-management training requires this service be provided by an education program that has achieved recognition by the American Diabetes Association or American Association of Diabetes Educators; the staff in such a program are multidisciplinary and include at least a registered dietician and an registered nurse with experiential preparation in education and diabetes management (Mensing, 2007 [R]). A number of studies involving a clinical pharmacist in programs with cardiac risk factors in select patients with diabetes have proven to be effective (Cioffi, 2004 [D]). Providers should be aware of culturally appropriate educational and community resources to support persons with diabetes and their families.

An education plan should be identified based on the needs of the individual and referral made to either an internal or external education resource. Periodic reassessment of educational goals is recommended (Lorig, 2001 [D]; Mensing, 2007 [R]).

See the Support for Implementation Section for a list of American Diabetes Association-recognized educa-tion programs available.

Components of self-management include:

• Description of the diabetes disease process and treatment options

• Goal-setting to promote health, and problem-solving for daily living

• Preventing, detecting and treating acute complications

• Preventing (through risk reduction behavior), detecting and adhering to treatments for chronic complications

• Self-monitoring blood glucose, ketones (when appropriate), and using results to improve control

• Incorporation of appropriate nutrition management (Barnard, 1994 [C])

• Incorporation of physical activity into lifestyle (Barnard, 1994 [C])

• Utilizing medications (if applicable) to maximize therapeutic effectiveness


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• Awareness of culturally appropriate community resources/support for persons with diabetes mellitus and their families and ability to access community resources

• Psychosocial adjustment of diabetes to daily life

• Promotion of preconception care, counseling and management during pregnancy, if applicable

Foot CareEducation should be tailored to patient's current knowledge, individual needs and risk factors. Patients should be aware of their risk factors and appropriate measures to avoid complications (American Diabetes Association, 2004f [R]; Mayfield, 1998 [R]). See Annotation #35, "Annual Assessment of Complications, Comprehensive Foot Exam with Risk Assessment."

Education should cover:

• Inspect feet daily for cuts, bruises, bleeding, redness and nail problems.

• Wash feet daily and dry thoroughly including between the toes.

• Do not soak feet unless specified by a health care provider.

• Be careful of hot water.

• Use of lotions, creams or moisturizer is acceptable, but do not use between the toes.

• Do not walk barefoot.

• Check shoes each day for objects that may have fallen inside, excessive wear or areas that may cause irritation.

• Avoid injuries from cutting toenails; avoid self-cutting calluses or corns.

• When to seek care

Community ResourcesThere is some evidence for the effectiveness of community-based diabetes self-management education and support. These programs may complement the care and education that are routinely part of standard medical practice, and may enhance a patient's ability to self-manage diabetes. The Task Force on Community Preventive Services, supported by the Centers for Disease Control and Prevention, recommends diabetes self-management education in community gathering places.

11. Set Personalized A1c Goal = A1c Less Than 7% or Individualized to a Goal Less Than 8% Based on Factors in 11aKey Points:

• Individual A1c and other treatment goals should be based on the risks and benefits for each patient. Set personalized A1c goal less than 7% or individualize to goal less than 8% based on complex patient factors.

A1c target in type 2 diabetes is aimed at reducing microvascular complications while not increasing risk of morbidity or mortality.

• All patients with type 2 diabetes should aim to achieve an A1c less then 8%. This will reduce microvasuclar disease and not increase risk substantially.



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• Most (many) patients with type 2 diabetes may derive additional benefit in reduction of microva-suclar disease by reaching a target A1c less than 7% (and not increase risks as long as the target is not A1c less than 6%).

[Conclusion Grade II: See Conclusion Grading Worksheet B – Annotation #11 (A1c)]

The work group defines high cardiovascular risk as the patient having two other cardiovascular risks (obesity, hypertension, dyslipidemia, smoking and proteinura). Alternative approachs to calculate cardiovascular risk include the Framingham equation, Archimedes and UKPDS.

The physician and patient should discuss and document specific treatment goals and develop a plan to achieve all desired goals. A multifactorial approach to diabetes care that includes emphasis on blood pressure, lipids, glucose, aspirin use, and non-use of tobacco will maximize health outcomes far more than a strategy that is limited to just one or two of these clinical domains (American Diabetes Association, 2009 [R]; Duckworth, 2009 [A]; Gaede, 2008 [A]; Holman, 2008 [A]).

For patients with type 2 diabetes and the following factors, an A1c goal of less than 8% may be more appro-priate than an A1c goal of less than 7% (Action to Control Cardiovascular Risk in Diabetes Study Group, The, 2008 [A]; ADVANCE Collaborative Group, The, 2008 [A]; Duckworth, 2009 [A]).

• Known cardiovascular disease or high risk cardiovascular risk.

• Inability to recognize and treat hypoglycemia, history of severe hypoglycemia requiring assis-tance.

• Inability to comply with standard goals, such a polypharmacy issues.

• Limited life expectancy or estimated survival of less than 10 years.

• Cognitive impairment.

• Extensive comorbid conditions such as renal failure, liver failure and end-stage disease complica-tions.

The benefits of a multifactorial approach to diabetes care are supported by the results of the Steno 2 Study of 160 patients with type 2 diabetes and microalbuminuria. Multifactorial interventions achieved a 50% reduction in mortality and significant reduction in microvascular complications five years after ending a 7.8-year multifactorial intervention that achieved A1c of 7.8%, low-density lipoprotein 83 mg/dL, blood pressure 131/73, compared to a conventional group that achieved A1c 9%, low-density lipoprotein 126 mg/dL and blood pressure 146/78 (Gaede, 2008 [A]). Results of this study are consistent with the need for reasonable blood sugar control with emphasis on blood pressure and lipid management.

Recently reported clinical trials have evaluated the impact of A1c less than 7% on macrovascular and microvascular complications of type 2 diabetes. These studies, the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular Disease: Preferax and Diamcron Modified Release Controlled Evaluation (ADVANCE), and VADT Trials, are the first that have ever achieved and maintained A1c less than 7% in their intensive treatment patients. A more detailed description of these trials is included in Conclusion Grading Worksheet B – Annotation #11 (A1c).

In the ACCORD Trial, excess mortality in the intensive group (A1c mean 6.4% vs. standard group A1c 7.5%) forced the safety board to discontinue the intensive treatment arm earlier than planned (Action to Control Cardiovascular Risk in Diabetes Study Group, The, 2008 [A]). There was one excess death for every 90 patients in the intensive group over a 3.5-year period of time. In the ADVANCE trial, intensive group patients achieved A1c 6.5% (vs. 7.5% in standard group) but had no reduction in cardiovascular complications or events. In the VADT trial, intensive group patients achieved A1c of 6.9% but had no significant reduction in cardiovascular events or microvascular complications compared to standard group patients who achieved



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A1c 8.4%. However, the VADT Trial was underpowered for its main hypothesis tests (Duckworth, 2009 [A]). In the ADVANCE trial, intensive group patients had less progression to proteinuria (one less patient advancing to proteinuria for every 100 people in the intensive group over a five-year period of time), but no fewer eye complications in the intensive group than in the standard group. ACCORD has not yet analyzed impact of A1c control on microvascular complications.

Recent follow-up data from the United Kingdom Prospective Diabetes Study of newly diagnosed patients with type 2 diabetes confirm major macrovascular and microvascular benefits of achieving A1c in the 7.1% to 7.3% range, vs. A1c of about 8% in the comparison groups (Holman, 2008 [A]). The United Kingdom Prospective Diabetes Study main trial included 3,867 newly diagnosed type 2 diabetes patients and showed over a 10-year period a 25% decrease in microvascular outcomes with a policy using insulin and sulfony-lureas that achieved a median A1c of 7.1%, compared to 7.9%. A subgroup of obese patients (n=1,704) treated with metformin and achieving a median A1c of 7.3% showed greater advantages over conventional treatment: a 32% reduction of diabetes-related end points (P=0.002), a 42% reduction of diabetes-related deaths (P=0.017), and a 36% reduction of all-cause mortality (P=0.011) (UK Prospective Diabetes Study Group, 1998b [A]; United Kingdom Prospective Diabetes Study Group, 1998d [A]).

Epidemiological studies supported the recommendation for intensive glycemic control to A1c below 7% to reduce microvascular and macrovascular disease, but the benefits have not been consistently demonstrated in randomized control trials. It is possible that some aspect of the medications used to achieve low A1c values in the ACCORD, ADVANCE and VADT trials offset the anticipated benefits. Of available glucose-lowering medications, only metformin and human insulins have been thoroughly vetted for long-term safety (Goldfine, 2008 [R]; Inzucchi, 2002 [M]; Selvin, 2008 [M]). Many recent reports have questioned the safety of rosiglitazone, which was widely used in ACCORD (Nissen, 2007 [M]; Winkelmayer, 2008 [B]). Furthermore, the microvascular benefits in recent trials (ADVANCE, VADT) have been fewer than in older trials, perhaps because of better background blood pressure and low-density lipoprotein control in recent trials.

Glycosylated hemoglobin assays provide an accurate indication of long-term glycemic control. A1c is formed by the continuous non-enzymatic glycosylation of hemoglobin throughout the lifespan of an eryth-rocyte. This assay yields an accurate measure of time-averaged blood glucose during the previous six to eight weeks.

There are various methodologies (e.g., HbA, A1c, glycated hemoglobin) for this assay. At present, there are no established criteria for use as a diagnostic test. Clinically it can assist in determining duration and severity of hyperglycemia and can help guide treatment.

Eating, physical activity or acute metabolic stress do not influence the A1c test. The test can be done at any time of day and does not require fasting.

Glucose should also be used to assess level of glycemic control, in addition to A1c. It is appropriate to determine need for medication changes based on blood glucose whenever this information is available.

• Self-monitoring blood glucose

Major clinical trials assessing the impact of glycemic control on diabetes complications have included self-monitoring blood glucose (SMBG) as part of multifactorial interventions, suggesting that self-monitoring blood glucose is a component of effective therapy (American Diabetes Association, 2007c [R]). However, there have been few large published studies done specifically to assess the link between self-monitoring blood glucose and A1c levels. The following table gives ranges of self-monitored glucose readings that would be expected for patients with the corresponding A1c levels.

Self-monitoring blood glucose allows patients to evaluate their individual response to therapy and assess whether glucose targets are being achieved. Results of self-monitoring blood glucose can be useful in



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preventing hypoglycemia and adjusting medications, medical nutrition therapy and physical activity (American Diabetes Association, 1994 [R]).

The frequency and timing of self-monitoring blood glucose should be dictated by the particular needs and goals of the individual patient. Patients with type 2 diabetes on insulin typically need to perform self-monitoring blood glucose more frequently than those not using insulin, particularly if using glucose readings to guide mealtime insulin dosing. It is recommended that patients using multiple insulin injec-tions perform self-monitoring blood glucose three or more times daily (American Diabetes Association, 2007c [R]). The optimal frequency and timing of self-monitoring blood glucose for patients with type 2 diabetes on oral agent therapy are not known but should be sufficient to facilitate reaching glucose goals. Self-monitoring blood glucose should be performed more frequently when adding or modifying therapy; two-hour postprandial glucose testing is useful in some patients. The role of self-monitoring blood glucose in stable diet-treated patients with type 2 diabetes is not known.

Because the accuracy of self-monitoring blood glucose is instrumental and user dependent, it is important for health care providers to evaluate each patient's monitoring technique. In addition, optimal use of self-monitoring blood glucose requires proper interpretation of the data. Patients should be taught how to use the data to adjust food intake, exercise or pharmacological therapy to achieve specific glycemic goals.

Examples of self-monitoring glucose goals, frequency and timing are (American Diabetes Association, 2007c [R]):

• Target preprandial plasma glucose values to a goal of 70-130 mg/dL for an A1c goal less than 7%. Target blood glucose readings could be higher or lower depending on individualized A1c goal.

• Average two-hour post-prandial plasma glucose values less than 140-180 mg/dL.

• Two-hour postmeal plasma blood glucoses can be helpful for adjusting mealtime medications. The target range for postmeal glucoses is controversial at this time, but a reasonable two-hour postprandial target is within 40 mg/dL higher than the preprandial reading.

• Average bedtime plasma glucose values are less than 120 mg/dL with a goal of 110-150 mg/dL.

• Bedtime glucose goals vary dependent on the patient's treatment program, risks for hypogly-cemia, and time after last meal.

• More than half of the plasma blood glucose readings should fall in the desired goal range.

Table 1. Ranges of self-monitored blood glucose values for various A1c goals

A1c Target Average Mean

Fasting Blood

Glucose*

Average Mean Post-

Prandial Blood

Glucose

Estimated Average

Blood Glucose**

< 6% < 100 < 140 126

7% 90-130 < 180 154

8% 120-160 < 210 182

9% 160-190 < 240 211

* It is not recommended to target fasting glucose values below 70 mg/dl.

** This average figures weigh both fasting and post-prandial blood glucose readings from continuous

glucose monitors or from 7-point daily testing.



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Table 1 was developed by the diabetes work group based on data currently available from studies of frequently monitored glucose values and will be modified if necessary as further studies become available.

13. Treatment Goals for Patients without Cardiovascular DiseaseKey Points:

• A major focus of diabetes care is to achieve the following treatment goals: use of statins in all adult type 2 diabetes patients if tolerated; statins should be titrated to achieve low-density lipoprotein cholesterol of less than 100 mg/dL without coronary artery disease, blood pressure less than 130/80 mmHg. Set personalized A1c goal = A1c less than 7% or individualized to goal of less than 8% based on risk factors. Daily aspirin use is optional for primary prevention of cardiovascular events.

• Consider statin, unless contraindicated

For patients with type 2 diabetes mellitus, consider the use of a statin. Randomized controlled trials, including a number of large trials, and observational data consistently show a benefit of statin therapy for patients with type 2 diabetes. Some studies also report that statin therapy was well tolerated in these patients. However, none of these studies was able to assess long-term effects of statin treat-ment/use. [Conclusion Grade I: See Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use)]. Evidence (Colhoun, 2004 [A]; Heart Protection Collaborative Study Group, 2002 [A]) and Adult Treatment Panel III consensus guidelines (Grundy, 2004 [R]) suggest that statins are beneficial for high-risk patients ages 40-80 years with a 10-year risk of cardiovascular event of more than 20%, even with baseline untreated low-density lipoprotein of less than 100 mg/dL. There is an online and a Palm format-downloadable cardiovascular risk calculator that is used in assessing 10-year risk of cardiovascular disease used in the Adult Treatment Panel III guideline report and this guideline on lipid management (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001 [R]). The links are:

Online calculator: http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof

Palm format (downloadable): http://hin.nhlbi.nih.gov/atpiii/riskcalc.htm.

[Conclusion Grade I: See Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use)] (Colhoun, 2004 [A]; Heart Protection Collaborative Study Group, 2002 [A]; Howard, 2008 [A]; Malmström, 2009 [A]; Newman, 2008 [A]; Robins, 2001 [A]; Settergren, 2008 [A])

• LDL less than 100 mg/dL

The low-density lipoprotein cholesterol goal for people with diabetes mellitus without coronary artery disease is less than 100 mg/dL.

Intensify statin or lipid-lowering medications to meet low-density lipoprotein cholesterol goals (LaRosa, 2005 [A]).

Three pathways to improve lipids are:

• Medical nutrition therapy

• Increased physical exercise

• Pharmacotherapy

Beneficial effects of statins on cardiovascular risk reduction may go beyond their effects on lipid levels. Diabetes is considered a coronary artery disease equivalent.



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There currently is little evidence for safety and efficacy of combination therapy with statins and other lipid drugs. National Institutes of Health-sponsored randomized controlled studies are currently underway to determine whether adding fibrates or niacin to statin therapy will lower the risk of cardiovascular events for patients with diabetes. ACCORD (fibrate plus statins in diabetes patients) results will be reported in early 2010, and AIM-HIGH (niacin plus statin) will be reported circa 2012.

Seventy to seventy-five percent of adult patients with diabetes die of macrovascular disease, specifically coronary, carotid and/or peripheral vascular disease. Dyslipidemia is a known risk factor for macrovas-cular disease. Patients with diabetes develop more atherosclerosis than patients without diabetes with the same quantitative lipoprotein profiles. In most diabetes patients, use of a statin can reduce major vascular events (HPS [A] 4S diabetes substantially (Pyorola, 1997 [A]).

High triglycerides and low high-density lipoprotein cholesterol levels are independent risk factors for cardiovascular disease in the patient with diabetes (American Diabetes Association, 2007c [R]). Indi-viduals with elevated triglycerides have significant cardiovascular risk reduction with the use of fibrates (Robins, 2001 [A]) or statins (Heart Protection Collaborative Study Group, 2003 [A]). While a number of studies support favorable changes in lipid profiles with niacin alone, randomized controlled trials considering hard cardiovascular outcomes are still underway (AIM-HIGH).

• Goals for blood pressure control: blood pressure less than 130/80 mmHg, emphasis on systolic blood pressure control (American Diabetes Association, 2007c [R]; Chobanian, 2003 [R])

Uncontrolled hypertension is a major cardiovascular risk factor that also accelerates the progression of diabetic nephropathy (Morrish, 1991 [B]). When hypertension is identified, it should be aggressively treated to achieve a target blood pressure of less than 130/80 mmHg. In many patients with diabetes, two or three or more antihypertensive agents may be needed to achieve this goal. The use of generic combination tablets (such as ACE plus calcium-channel blocker, or else beta-blocker plus diuretic) can reduce the complexity of the regimen and out-of-pocket costs. See the Blood Pressure Control algorithm.

For patients with type 2 diabetes mellitus, the systolic blood pressure goal is less than 130 mmHg and the diastolic blood pressure goal is less than 80 mmHg. [Conclusion Grade II: See Conclusion Grading Worksheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)] (Hansson, 1998 [A]; UK Prospective Diabetes Study [A], 1998c; UK Prospective Diabetes Study, 1998e [A]). ADVANCE trial BP results, also showed major benefits of SBP of 134 mmHg in patients with type 2 diabetes.

• Aspirin/antiplatelet medication optional (Bhatt, 2002 [A])

Patients with type 2 diabetes are at a significantly increased risk for development of heart disease (American Diabetes Association, 2007c [R]). There is insufficient evidence to support aspirin use in the primary prevention of cardiovascular events in patients with type 2 diabetes, although there is no evidence of significant harm. However, there is sufficient evidence to support the use of aspirin for secondary prevention of cardiovascular events in patients with type 2 diabetes. [Conclusion Grade I: See Conclusion Grading Worksheet E – Annotations #13, 14 (Aspirin Use)]. Some recent trials of aspirin use in diabetes have shown less benefit than older trials (perhaps due to better background A1c, blood pressure, and low-density lipoprotein control and lower smoking rates in recent trials) (Belch, 2008 [A]; Ogawa, 2008 [A]). There are significant limitations identified in these studies, and more definitive studies would be helpful. [Conclusion Grade I: See Conclusion Grading Worksheet E – Annotations #13, 14 (Aspirin Use)]. Therefore, based on current evidence, low-dose aspirin is considered optional for primary prevention.

On September 8, 2006, the Food and Drug Administration issued a Safety Information and Adverse Event Report regarding the concomitant use of aspirin and ibuprofen. With occasional use of ibuprofen, there is likely to be minimal risk from any attenuation of the antiplatelet effect of low-dose aspirin, because



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29

of the long-lasting effect of aspirin on platelets. Recommendations include taking immediate-release aspirin (not enteric-coated) 30 minutes or longer prior to taking ibuprofen (400 mg). If ibuprofen is taken first, aspirin should not be taken for at least eight hours after ingestion of ibuprofen.

• Goals for tobacco use-smoking cessation, if indicated

Tobacco smoking increases risk of macrovascular complications about 4%-400% in adult with type 2 diabetes and also increases risk of macrovascular complications. Although only about 14% of adult with diabetes in Minnesota are current smokers, in these patients, smoking cessation is very likely to be the single most beneficial intervention that is available, and should be emphasized by providers as described below.

- Identify and document tobacco use status.

- Treat every tobacco user. If the patient is unwilling, the clinician should implement motivational treatments.

- Individual, group and telephone counseling are effective, and their effectiveness increases with treatment intensity.

- Practical counseling (problem-solving/skills training and social support delivered as part of the treatment) are especially effective counseling strategies and should be implemented by clinicians.

- Numerous effective medications are available.

- The combination of counseling and medication is more effective than either alone. Therefore, clini-cians should encourage all individuals making a quit attempt to use both.

- Telephone quit line counseling is effective. Therefore, clinicians and health care delivery systems should ensure patient access to quit lines and promote their use.

- Tobacco dependence treatments are both clinically effective and cost effective. Effective interven-tions require coordinated interventions. Just as the clinician must intervene with the patient, so must the health care administrator, insurer and purchaser foster and support tobacco intervention as an integral element of health care delivery.

Numerous effective pharmacotherapies for smoking cessation now exist. Except in the presence of contrain-dications, these may be used with all patients attempting to quit smoking. Please see the ICSI Preventive Services in Adults guideline for additional information.

Tobacco telephone quit lines: HHS National Quit line (1-800-QUITNOW) or 1-800-784-8669; other local quit lines may be available.

14. Treatment Goals for Patients with Cardiovascular DiseaseKey Points:

• A major goal of diabetes care is to achieve the following treatment goals: use of statins in all adult type 2 diabetes patients if tolerated; statins should be titrated to achieve low-density lipoprotein cholesterol of less than 70 mg/dL with coronary artery disease, blood pressure less than 130/80 mmHg. Set personalized A1c goal = A1c less than 7% or individualized to goal of less than 8% based on risk factors. Daily aspirin use is recommended in patients with cardiovascular disease.



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• Consider statin, unless contraindicated

For patients with type 2 diabetes mellitus, consider the use of a statin. Randomized controlled trials, including a number of large trials, and observational data consistently show a benefit of statin therapy for patients with type 2 diabetes. Some studies also reported that statin therapy was well tolerated in these patients. However, none of these studies was able to assess long-term effects of statin treatment/use. [Conclusion Grade I: See Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use)] (Colhoun, 2004 [A]; Heart Protection Collaborative Study Group, 2002 [A]; Howard, 2008 [A]; Malm-ström, 2009 [A]; Newman, 2008 [A]; Robins, 2001 [A]; Settergren, 2008 [A])

• LDL less than 70 mg/dL

The low-density lipoprotein cholesterol goal for people with diabetes mellitus with coronary artery disease is less than 70 mg/dL.

Intensify statin or lipid-lowering medications to meet low-density lipoprotein cholesterol goals (LaRosa, 2005 [A]).

Use of moderate- to high-dose statins or other low-density lipoprotein cholesterol-lowering medications as needed to achieve a low-density lipoprotein cholesterol value less than 70 mg/dL is recommended for patients with coronary heart disease (Cannon, 2004 [A]; Pyorala, 1997 [A]).

Three pathways to improve lipids are:

• Medical nutrition therapy

• Increased physical exercise

• Pharmacotherapy

There currently is no evidence for safety and efficacy of combination therapy with statins and other lipid drugs. National Institutes of Health-sponsored randomized controlled studies are currently underway to determine whether adding fibrates or niacin to statin therapy will lower the risk of cardiovascular events for patients with diabetes.

Seventy to seventy-five percent of adult patients with diabetes die of macrovascular disease, specifically coronary, carotid and/or peripheral vascular disease. Dyslipidemia is a known risk factor for macrovas-cular disease. Patients with diabetes develop more atherosclerosis than patients without diabetes with the same quantitative lipoprotein profiles. In most diabetes patients, use of a statin can reduce major vascular events (HPS [A] 4S diabetes substantially (Pyorola, 1997 [A]).

High triglycerides and low high-density lipoprotein cholesterol levels are independent risk factors for cardiovascular disease in the patient with diabetes (American Diabetes Association, 2007c [R]). Indi-viduals with elevated triglycerides have significant cardiovascular risk reduction with the use of fibrates (Robins, 2001 [A]) or statins (Heart Protection Collaborative Study Group, 2003 [A]). While a number of studies support favorable changes in lipid profiles with niacin alone, randomized controlled trials considering hard cardiovascular outcomes are still underway (AIM-HIGH).

• Goals for blood pressure control: blood pressure less than 130/80 mmHg, emphasis on systolic blood pressure control (American Diabetes Association, 2007c [R]; Chobanian, 2003 [R])

Uncontrolled hypertension is a major cardiovascular risk factor that also accelerates the progression of diabetic nephropathy (Morrish, 1991 [B]). When hypertension is identified, it should be aggressively treated to achieve a target blood pressure of less than 130/80 mmHg. In many diabetes patients, two or three or more antihypertensive agents may be needed to achieve this goal. The use of generic combina-tion tablets (such as ACE plus calcium-channel blocker, or else beta-blocker plus diuretic) can reduce the complexity of the regimen and out-of-pocket costs. See the Blood Pressure Control algorithm.



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For patients with type 2 diabetes mellitus, the systolic blood pressure goal is less than 130 mmHg and the diastolic blood pressure goal is less than 80 mmHg. [Conclusion Grade II: See Conclusion Grading Worksheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)] (Hansson, 1998 [A]; UK Prospective Diabetes Study [A], 1998c; UK Prospective Diabetes Study, 1998e [A]).

• Aspirin/antiplatelet medication use unless contraindicated (Bhatt, 2002 [A])

There is insufficient evidence to support aspirin use in the primary prevention of cardiovascular events in patients with type 2 diabetes, although there is no evidence of significant harm. However, there is sufficient evidence to support the use of aspirin for secondary prevention of cardiovascular events in patients with type 2 diabetes. [Conclusion Grade I: See Conclusion Grading Worksheet E – Annota-tions #13, 14 (Aspirin Use)]

If aspirin is contraindicated, consider use of clopidogrel or ticlopidine. For more information, please refer to the ICSI Stable Coronary Artery Disease guideline and the Antithrombotic Therapy Supplement.

On September 8, 2006, the Food and Drug Administration issued a Safety Information and Adverse Event Report regarding the concomitant use of aspirin and ibuprofen. Health care professionals should counsel patients about the appropriate timing of ibuprofen dosing if they are taking aspirin for cardiopro-tective effects. With occasional use of ibuprofen, there is likely to be minimal risk from any attenuation of the antiplatelet effect of low-dose aspirin, because of the long-lasting effect of aspirin on platelets. Recommendations include taking immediate-release aspirin (not enteric-coated) 30 minutes or longer prior to taking ibuprofen (400 mg). If ibuprofen is taken first, aspirin should not be taken for at least eight hours after ingestion of ibuprofen.

For more information, please refer to the information listed on the Food and Drug Administration's Web site for a complete copy of the alert and cited references.

http://www.fda.gov/medwatch/safety/2006/safety06.htm#aspirin.

• Goals for tobacco use-smoking cessation, if indicated

Tobacco smoking increases risk of macrovascular complications about 4%-400% in adult with type 2 diabetes, and also increases risk of macrovascular complications. Although only about 14% of adult with diabetes in Minnesota are current smokers, in these patients, smoking cessation is very likely to be the single most beneficial intervention that is available, and should be emphasized by providers as described below.

- Identify and document tobacco use status.

- Treat every tobacco user. If the patient is unwilling, the clinician should implement motivational treatments.

- Individual, group and telephone counseling are effective, and their effectiveness increases with treatment intensity.

- Practical counseling (problem-solving/skills training and social support delivered as part of the treatment) are especially effective counseling strategies and should be implemented by clinicians.

- Numerous effective medications are available.

- The combination of counseling and medication is more effective than either alone. Therefore, clini-cians should encourage all individuals making a quit attempt to use both.

- Telephone quit line counseling is effective. Therefore, clinicians and health care delivery systems should ensure patient access to quit lines and promote their use.



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- Tobacco dependence treatments are both clinically effective and cost effective. Effective interven-tions require coordinated interventions. Just as the clinician must intervene with the patient, so must the health care administrator, insurer and purchaser foster and support tobacco intervention as an integral element of health care delivery.

15. Are Treatment Goals Met?Major long-term goals of care in type 2 diabetes are cardiovascular disease prevention (see the Blood Pres-sure Control algorithm) and achieving optimal glycemic control (see Glycemic Control algorithm).

Setting initial goals that are achievable, however modest they may be, may encourage patients to take further steps along the way to the more ambitious long-term goals.

Goals and progress toward agreed-upon goals should be briefly reviewed at each office visit for diabetes. Adjustment of goals will likely be required over time, and patient involvement in this process can increase levels of patient involvement in care, give patients a greater sense of control of their diabetes, and allow flexibility in management of diabetes during periods of high stress or major life transitions.

16. Treatment Goals Not MetModify Treatment Based on Appropriate Related Guideline

• Prevention and Management of Obesity (Mature Adolescents and Adults)

• Hypertension Diagnosis and Treatment

• Lipid Management in Adults

• Major Depression in Adults in Primary Care

See Glycemic Control and Blood Pressure Control Algorithms

Consider Referral to Diabetes Care Team or Specialists• Assess patient adherence

Non-adherence with medications can limit the success of therapy and help to explain why a patient is not achieving treatment goals. To screen for non-adherence, clinicians can ask patients open-ended, non-threatening questions at each office visit. The assessment should include probes for factors that can contribute to non-adherence (fear of adverse reactions, misunderstanding of chronic disease treatment, depression, cognitive impairment, complex dosing regimens, or financial constraints).

• Assess the patient's knowledge of his/her condition and his/her expectations for treatment.

• Assess the patient's medication administration process.

• Assess the patient's barriers to adherence.

Interventions to enhance medication adherence should be directed at risk factors or causes of non-adherence. Interventions may include simplifying the medication regimen, using reminder systems, involving family or caregivers in care, involving multiple disciplines in team care, providing written and verbal medication instructions, setting collaborative goals with patients, and providing education about medications (including potential adverse effects) and about diabetes in general (Nichols-English, 2000 [R]).



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• Evaluate for depression

There is a substantial increase in the prevalence of depression among people with diabetes as compared to the general adult population (Anderson, 2001 [M]). Self-administered or professionally administered instruments (such as the PHQ-9) are useful adjuncts to the clinical interview in the identification of depression. Depression impacts the ability of a person with diabetes to achieve blood glucose control, which in turn impacts the rate of development of diabetes complications (DeGroot, 2001 [M]; Lustman, 2001 [R]).

Identification and management of depression is an important aspect of diabetes care. Self-administered or professionally administered instruments, such as PHQ-9, are useful adjuncts to the clinical interview in the identification of depression. The ICSI Major Depression in Adults in Primary Care guideline provides more suggestions for the identification and mangement of depression. Intervention studies have demonstrated that when depression is treated, both quality of life and glycemic control improve. Counseling may be effective, especially among those who are having difficulty adjusting to the diag-nosis of diabetes or are having difficulty living with diabetes. Pharmacotherapy for depression is also effective.

• Diabetes care team

Assure the patient has an adequate care team.

Diabetes educator

Consultation with a diabetes educator is suggested if the patient is having difficulty adhering to a nutri-tion, exercise and medication regimen and the patient is having difficulty adhering to, or accurately completing, blood glucose monitoring or may need answers to some questions.

Every primary care physician must develop a relationship with a diabetes education program to provide other options for management. The American Diabetes Association publishes a list of recognized educational programs in each state. These programs may be staffed with endocrinologists or primary care providers plus diabetes educators including dietitians, nurses and other health care providers who are Certified Diabetes Educators or have didactic and experiential expertise in diabetes care and educa-tion.

Endocrinologist/nephrologist

Most type 2 diabetes management can be managed by a primary care physician with periodic consultation as needed by an endocrinologist.

Consultation with a specialist is suggested if persistent proteinuria, worsening microalbuminuria and elevation in serum creatinine or blood urea nitrogen, or hypertension unresponsive to treatment is seen. For additional discussion, see Annotation #36, "Treatment and Referral for Complications, Nephropathy."

Endocrinologist/neurologist

Consultation with a specialist is suggested if neuropathy progresses and becomes disabling.

Endocrinologist/cardiologist/hypertension specialist

Consultation with a specialist is suggested if blood pressure is refractory to treatment, the patient has marked associated postural hypotension or symptoms of coronary artery disease.

Foot care specialist

A consultation with a specialist is suggested if the patient is unable to care properly for his/her own feet, needs prescriptive footwear and/or more serious problems such as foot deformities (e.g., Charcot deformity), infected lesions, and ulcers, deformed nails or thick calluses are present.



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Vascular Specialist/Surgeon

Consider referral if patient has symptoms of peripheral vascular disease such as loss of pulses and/or clau-dication.

Glycemic Control Algorithm Annotations

18. Glycemic Control AlgorithmMedical nutrition therapy may be all that is required to treat diabetes, especially for the patient with early mild symptomatic disease. Medical nutrition therapy should be maintained throughout the course of the disease, even as pharmacologic agents are used. Oral agent medications are generally used if medical nutri-tion therapy alone does not succeed in obtaining patients' goals within a reasonable time frame, usually no longer than two to three months. Metformin plus lifestyle treatment is also a reasonable initial therapy at the time of diagnosis, given the low risk of hypoglycemia and the benefits of metformin shown in both prediabetes and diabetes (Nathan, 2006 [R]).

At the time of diagnosis, if patients have severe symptomatic disease, insulin should be initiated. With appropriate educational support and care, the risks of insulin may not differ from many oral agents. In some circumstances when glucose intolerance is significant and the patient is unwilling to consider insulin or it is not felt to be appropriate, the initiation of combinations of oral agents can be appropriate. Insulin is indicated when there is a failure to achieve treatment goals with oral agents.

It is important to remember that patients can move both ways on the Glycemic Control algorithm, e.g., they can move off of specific pharmacologic therapies as lifestyle changes are made that improve glycemic control. Diabetes is a progressive disease, however, and the use of pharmacologic agents will likely become necessary in the majority of patients, even if they are able to follow through with nutrition and physical activity recommendations (Turner, 1999 [A]).

19. Pharmacologic Agent(s) – Which Is Best?Key Points:

• Age and weight of the patient, as well as presence of renal dysfunction, cardiopulmonary comorbidities and hepatic disease must be considered when choosing pharmacologic agents.

Only general guidelines can be given when deciding about which pharmacologic agent will be best for a specific patient. While each patient presents with unique circumstances, the work group offers the following clinical circumstances to consider.

Age of PatientIt is important to recognize that risks of medications are often increased with advancing age, but this does not justify the withholding of medications that may reduce the symptoms of polyuria, nocturia and frequent visits to the bathroom that may place the patient at risk of hip fracture or falls.

With age, decline in renal function is often not reflected in a measurable change in serum creatinine because of an accompanying decline in muscle mass. Because of this, metformin should be used with caution in elderly patients (over age 80).

Decline in ventricular function and risks for volume overload can be occult in the elderly and may become clinically apparent with the use of thiazolidinediones.



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In select circumstances, because of the risks of hypoglycemia, variable diet habits and renal clearance and function, it may be safer to consider initial low-dose, short-acting sulfonylurea (e.g., glipizide or repaglinide/nateglinide when a meal is eaten).

Weight of the PatientType 2 diabetes is often associated with insulin resistance and weight gain. Metformin, acarobose, exenatide, sitagliptin and human amylin are more often associated with weight loss or weight maintenance. Due to its weight benefits as well as general tolerability, lower cost and proven benefits in UK Prospective Diabetes Study Group, metformin is recommended for most diabetes patients with type 2 diabetes unless contrain-dicated. Insulin and thiazolidinediones may be associated with weight gain (United Kingdom Prospective Diabetes Study Group, 1998b [A]).

Renal DysfunctionRenal dysfunction increases the risk for hypoglycemia, in particular with the use of oral hypoglycemic agents.

Metformin and alpha glucosidase inhibitors should not be used.

Thiazolidinediones may be considered, but the potential risks of fluid retention and increased risk of cardiac events need to considered.

Short-acting oral agents glipizide, glimepiride (in which serum levels have been noted to decrease in mild renal failure), repaglinide or nateglinide may be preferred if an oral agent is felt to be necessary in the face of renal dysfunction.

Insulin may be the safest when serum creatinine is greater than 1.8 mg or creatinine clearance is less than 60 mL/min.

Cardiopulmonary ComorbiditiesMetformin should be used with caution for patients with conditions that predispose them to risk of hypoxia such as congestive heart failure, chronic obstructive pulmonary disease or obstructive sleep apnea. Metformin should be promptly discontinued in situations of cardiovascular collapse from acute congestive heart failure, acute myocardial infarction or any other cause.

Patients started on thiazolidinediones should be instructed to report signs of lower extremity swelling, rapid weight gain, and shortness of breath. Risk of thiazolidinediones needs to be discussed and documented before using in patients with cardiovascular risks. Please see the thiazolidinediones warning for more information.

Short-acting sulfonylurea (e.g., glipizide), repaglinide/nateglinide, and the cautious use of long-acting sulfonylureas agents or insulin may be safest.

Hepatic DiseaseHepatic disease or insufficiency increases the risks of lactic acidosis and hypoglycemia and influences the metabolism of many oral medications.

Metformin and thiazolidinediones should not be used if alanine aminotransferase (ALT) is 2.5-3 times normal upper limits.

First-generation sulfonylureas, glipizide and glyburide have some component of hepatic metabolism and should be used with caution because of the risks of hypoglycemia. Insulin would be considered safest.



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20. Prescribe Insulin Therapy• Insulin programs should be individualized based on the patient's lifestyle, treatment goals and self-

monitoring blood glucose. Many patients can be taught to interpret self-monitoring blood glucose results and adjust insulin doses (American Diabetes Association, 2004c [R]).

• Total dose ranges from 5 units/day to several hundred units/day.

• Average insulin doses are 0.6-0.8 units/kg of body weight per day.

• Obese patients often require doses equal to or exceeding 1.2 units/kg.

• Meal times and snacks should be consistent. Synchronize insulin with food intake patterns.

Time Course of Action of Insulin Preparations

Insulin Preparations Onset of

Action

Peak Action Duration of

Action

Cost

Short-Acting Regular 30 min. 2-5 hours 5-8 hours $$

Rapid-Acting Lispro

Aspart

Glulisine

15 min.

15 min.

15 min.

30-90 min.

1-3 hours

50-100 min.

2-4 hours

3-5 hours

5 hours

$$$$

$$$$

$$$$

Intermediate-

Acting

NPH 1-3 hours 6-12 hours 16-24 hours $$$

Long-Acting Detemir

Glargine

1 hour

1 hour

**

**

Up to 24 hours

24 hours

$$$$

$$$$

Mixtures Humalog® mix (75/25) or Humalog® mix (50/50)

Novolog® mix (70/30)

NPH and Regular

(70/30; 50/50)

15 min.

15 min.

30 min.

30-240 min.

60-240 min.

2-12 hours

16-24 hours

16-24 hours

16-24 hours

$$$$

$$$$

$$$

Source: Compiled from pdr.net

Cost is based on average wholesale price (AWP) of 30-day supply or one vial of injectible

drug.

Cost Indicators:

$ = $0 - $20

$$ = $21 - $40

$$$ = $41 - $60

$$$$ = $61 - $100

$$$$$ = $101 - $500

$$$$$$ = greater than $500

Note: Lente and Ultralente are no longer being manufactured and have been removed from this table.

• This table summarizes the typical time course of action of various insulin preparations. These values are highly variable among individuals. Even in a given patient, these values vary depending

on the site and depth of injection, skin temperature and exercise.

• No pronounced peak: small amounts of insulin are slowly released resulting in a relatively constant concentration/time profile over 24 hours.



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• Rapid-acting insulin should not be taken more than 15 minutes before meals in contrast to regular insulin, which should ideally be taken at least 30 minutes before a meal to better match the insulin peak action with postmeal hyperglycemia.

• Patients who are testing their glucose before meals and adjusting insulin doses to match meals may find rapid-acting insulin to be more effective, although generally studies have not shown an improvement in A1c when compared to regular insulin taken according to package insert (30-45 minutes preprandial).

• Effective use of rapid-acting insulin usually requires the addition of basal intermediate or long-acting insulin.

• There are several devices available on the market for the administration of insulin (e.g., insulin pump, insulin pen).

• Insulin pump therapy may be helpful for patients who are interested in more intensified management of blood glucose and want more flexibility, or if pregnancy is desired. Candidates for pump therapy should be evaluated by an endocrinologist or diabetes specialist to assess patient understanding, self-care knowledge including medical nutrition therapy, responsibility and commitment. Insulin pump therapy is more commonly used in type 1 patients, but is also being used by some type 2 patients.

• Please note the work group left the brand names for Humalog® and Novolog® in the table. The generic mix is as follows:

- Humalog mix: lispro protamine suspension/lispro injection

- Novolog mix: aspart protamine suspension/aspart injection

• Every facility needs to evaluate insulin safety per their specific situation.

22. Prescribe Non-Insulin AgentsPlease consult the manufacturer's product labeling insert for full prescribing information.

If not contraindicated, metformin is the preferred initial oral agent for type 2 diabetes due to low cost, low risk of hypoglycemia and side effects, and lack of associated weight gain. If metformin is contraindicated, sulfonylureas and glitazones are acceptable secondary choices for oral agents. Sulfonylureas have the advantage of being relatively inexpensive, and glitazones are contraindicated in congestive heart failure (Nathan, 2006 [R]).

For the following tables, cost is based on average wholesale price (AWP) of 30-day supply. Cost Indica-tors:

$ = $0 - $20$$ = $21 - $40$$$ = $41 - $60$$$$ = $61 - $100$$$$$ = $101 - $500$$$$$$ = greater than $500



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Metformin

Drug Name (Trade Name)

Usual starting

dose

Usual maximum clinically effective dose

per day

Maximum dose per day

Cost

Metformin (regular release)

500 mg daily or twice daily

1,000 mg twice daily 2,550 mg daily or

850 mg three times a day

$$*

Metformin (extended release)

500 mg daily with evening meal

2,000 mg daily or 1,000 mg twice daily

2,000 mg daily or 1,000 mg twice daily

$$

EFFICACY

• The A1c lowering commonly achieved with metformin is 1.5%-2.0%.

• Absorption and bioavailability of metformin (extended release) 2,000 mg daily is similar to that of metformin 1,000 mg twice daily. Costs favor the use of metformin for patients who can manage twice-daily dosing.

• The major effect may be reducing hepatic glucose production.

Metformin is indicated for treatment of type 2 diabetes as monotherapy or in combination with sulfonylureas or insulin.

SAFETY

• Metformin is contraindicated in patients with known hypersensitivity, renal disease, congestive heart failure (treated with medications), acute or chronic metabolic acidosis (including diabetic ketoacidosis).

• Do not use metformin in renal disease (creatinine greater than or equal to 1.5 mg/dL in men, creatinine greater than or equal to 1.4 mg/dL in women) because of possible lactic acidosis. In patients over age 80, check a creatinine clearance and use with caution. Even temporary reductions in renal function (e.g., pyelography or angiography) can cause lactic acidosis.

• Do not use for patients with COPD, severe hepatic disease or alcoholism.

• Side effects may be transient and can include metallic taste, diarrhea, nausea and anorexia.

• The use of metformin in pregnancy or lactation is not recommended.

• As monotherapy, metformin does not cause hypoglycemia.

• Intramuscular contrast studies with indicated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, metformin should be temporarily discontinued at the time or prior to any such study and withheld for 48 hours subsequent to the procedure. Reinstitute only after renal function has been reevaluated and found to be normal.


* Average wholesale price indicates a cost of $$; however, regionally this product is available for $.



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Second-Generation Sulfonylureas

Drug Name

(Trade

Name)

Duration Usual

starting

dose

Usual

start

dose

for

elderly

Usual

maximum

clinically

effective

dose

Maximum

dose per

day

Cost

Glimepiride 24 hr. 1-2 mg/d 1-2

mg/d

4 mg/d 8 mg/d $

Glipizide (regular

release)

10-24 hr. 5 mg/d 2.5 mg/d

10 mg twice daily

40 mg/d $

Glipizide

(extended release)

24 hr. 5 mg/d 5 mg/d 10 mg/d 20 mg/d $

Glyburide

(regular release)

18-24 hr. 2.5 mg-5

mg/d

1.25

mg/d

5 mg twice

daily

20 mg/d $

Glyburide

(micronized)

18-24 hr. 1.5-3

mg/d

0.75

mg/d

6 mg twice

daily

12 mg/d $

EFFICACY

• The A1c lowering commonly achieved with sulfonylureas is 1.5%-2.0%.

• The dose should be increased every one to two weeks until satisfactory glycemic control or the maximum dose is reached.

• There are no major differences between sulfonylureas with respect to effectiveness in

controlling hyperglycemia. Switching from one to another is rarely beneficial in improving hyperglycemia.

SAFETY

• These agents are contraindicated in diabetic ketoacidosis and in patients with known hypersensitivity to sulfonylureas.

• There are rare cross-sensitivities for patients with sulfa allergies.

• These agents should be used with caution for patients with hepatic or renal disease.

• Glipizide/or glimepiride may be relatively safer than glyburide patients with mild renal impairment.

• Hypoglycemia risk increases with impaired renal function. Glimepiride may cause less hypoglycemia in these circumstances.

• Glyburide has the highest rate of hypoglycemia of the sulfonylureas listed.




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Alpha Glucosidase Inhibitors



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41

Dipeptidyl Peptidase-4 (DPP-4) Inhibitor


Drug Name (Trade name)

Usual starting

dose

Usual maximum clinically

effective dose


Cost

Sitagliptin 100 mg once daily

100 mg once daily 100 mg once daily $$$$$

EFFICACY

• Slows the inactivation of incretins, hormones that are normally released in the gut throughout the day and increased after meals. Incretins increase insulin release from pancreatic beta cells, and lower glucagon secretion from pancreatic alpha cells.

• Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

• The A1c lowering commonly achieved with sitagliptin is 0.6-0.8 mg/dL. • Sitagliptin is indicated for monotherapy and as combination therapy (metformin,

glimepiride, glimepiride plus metformin, or a TZD). • Sitagliptin has not been studied in combination with insulin. • Can be taken with or without food.

SAFETY

• Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating sitagliptin and periodically thereafter.

o Moderate renal disease (start 50 mg once daily): CrCl ! 30 to < 50 mL/min; ~Serum Cr levels [mg/dL] – Men: > 1.7– " 3.0; Women: > 1.5 - " 2.5

o Severe and ESRD (start 25 mg once daily): CrCl < 30 mL/min: ~Serum Cr levels [mg/dL] – Men: > 3.0; Women: > 2.5; or on dialysis

• When used with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.

• Side effects reported in more than 5% of patients and more often than placebo were nasopharyngitis, upper respiratory tract infections, and headache.

• Safety and effectiveness of sitagliptin in children under 18 years have not been established.

• There are no adequate and well-controlled studies in pregnant women. • Hypoglycemia was similar to placebo (1.2% versus 0.9%).

• Studies addressing long-term safety are not available.



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Meglitinides (Short-Acting Secretagogues)


Usual starting dose Maximum dose per day Cost

Repaglinide 0.5 mg/meal with A1c less than 8% or no previous treatment

1 or 2 mg/meal with A1c greater than 8% or on other oral agent

4 mg/meal or 16 mg/day $$$$$

Nateglinide 60-120 mg three times a day before meals

120 mg/meal/day $$$$$

EFFICACY

• The average A1c lowering commonly achieved is 0.5%.

• The mechanism of action of these agents is to stimulate insulin secretion (similar to sulfonylureas).

• These agents have a short duration of action, one to four hours.

• These agents are usually taken 15 minutes before meals (range of 0-30 minutes).

• These agents are indicated for use in combination with metformin or TZDs.

SAFETY

• The major side effect of these agents is hypoglycemia, but the incidence may be less common than with sulfonylureas.

• Skip the dose if the meal is not eaten.

• Doses of nateglinide should be adjusted for hepatic impairment.

• Administration of gemfibrozil significantly increases repaglinide blood levels, which may lead to hypoglycemia. Avoid concomitant use of gemfibrozil and repaglinide.




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Glucagon-like Peptide 1 (GLP-1) Agonist:


Indications Onset of action

Peak action

Duration of action

Usual starting dose


Cost

Exenatide injection

Type 2 0-10 min. 2.1 hrs.

6-10 hrs. 5 mcg subcutaneous twice daily

10 mcg subcutaneous twice daily after one month

$$$$$

Mechanism of Action

• Stimulates glucose-dependent release of insulin and suppresses glucagons levels.

1. Modulation of gastric emptying 2. Prevention of the postprandial rise in plasma glucagons 3. Satiety leading to decreased caloric intake and potential weight loss

EFFICACY

• Intended for people with type 2 diabetes who are on oral medication but not achieving good blood sugar control. Offers an alternative option before starting insulin.

• Must be administered within the 60-minutes before the morning and evening meals. It should not be administered after a meal.

• When this agent is added to sulfonylurea therapy, a reduction in the dose of sulfonylurea may be needed to reduce the risk of hypoglycemia.

• Advantages over insulin are yet unclear, since like insulin, it must be injected twice daily. • Improves A1c by an average of 0.9% and lowers postprandial glucose.

SAFETY

• Contraindicated in patients with known hypersensitivity to this product or any of its components. • Is not a substitute for insulin in insulin-requiring patients. • Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. • Not recommended for use in patients with ESRD or severe renal impairment (CrCl less than 30 mL/min). • Not recommended in patients with severe gastrointestinal disease because its use is commonly associated with

gastrointestinal adverse effects, including nausea, vomiting and diarrhea. • Caution in patients receiving oral medications that require rapid gastrointestinal absorption. • For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and

antibiotics, patients should be advised to take those drugs at least one hour before exenatide injection. • Weight loss is often associated with use of this agent, especially when used concomitantly with metformin. • Exenatide use has been associated with reports of pancreatitis, although a causal relationship has not to this point

been established.




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Synthetic Analog of Human Amylin


Indications Onset of

action

Peak action

Duration of action

Usual starting dose


Cost

Pramlintide acetate injection

Type 1 and 2 diabetes

15-30 min.

20-27 min.

3-4 hrs. Type 2 : 60 mcg subcutaneous/meals

Type 2 : 120 mcg subcutaneous

$$$$$

Mechanism of Action

• Acting as an amylinomimetic agent has the following effects: 1. Modulation of gastric emptying 2. Prevention of the postprandial rise in plasma glucagons 3. Satiety leading to decreased caloric intake and potential weight loss

EFFICACY

• Indicated as an adjunct treatment in patients with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy, and it is used with or without a sulfonylurea and/or metformin.

• May decreases A1c by an average of 0.4% and may observe weight loss of less than 1 kg at six months.

• Must be administered immediately prior to each major meal.

• Reduce preprandial, rapid-acting or short-acting insulin dosages, including fixed-mix insulins by 50%.

• The agent may be considered in highly motivated patients willing to add two to four injections and more frequent glucose monitoring to their regimen.

SAFETY

• Contraindicated in patients with a known hypersensitivity to any of its components, including metacresol.

• Should only be considered in patients with insulin-using type 2 or type 1 diabetes who have failed to achieve adequate glycemic control despite individualized insulin management and are receiving ongoing care under the guidance of a health care professional skilled in the use of insulin and supported by the services of diabetes educator(s).

• Before initiation of therapy, A1c, recent glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weights should be reviewed.

• Patients meeting any of the following criteria should not be considered for pramlintide therapy: - Poor adherence with current insulin regimen - Poor adherence with prescribed self-blood glucose monitoring - A1c greater than 9% - Recurrent severe hypoglycemia requiring assistance during the past six months - Presence of hypoglycemia unawareness - Confirmed diagnosis of gastroparesis - Require the use of drugs that stimulate gastrointestinal motility - Require the use of drugs that slow the intestinal absorption of nutrients - Pediatric patients

• Primlintide alone does not cause hypoglycemia (without the concomitant administration of insulin). However, when it is co-administered with insulin therapy, there is an increase risk of insulin-induced severe hypoglycemia. Therefore, prescribe frequent pre- and postmeal glucose monitoring combined with an initial 50% reduction in premeal doses of short-acting insulin when starting pramlintide to reduce the occurrence of hypoglycemia.

• Its use is commonly associated with gastrointestinal adverse effects, including nausea, anorexia and vomiting.

• When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness, the agent should be administered at least one hour prior to two hours after primlintide injection.

• This product and insulin should always be administered as separate injections and never be mixed. Mixing will alter the pharmacokinetics parameters of primlintide.




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Thiazolidinediones (TZDs)


Usual starting dose Maximum dose per day Cost

Pioglitazone 15 or 30 mg once daily 45 mg daily $$$$$

Rosiglitazone 2 mg daily or twice daily 4 mg twice daily or 8 mg daily $$$$$

EFFICACY

• The A1c lowering commonly achieved with thiazolidinediones is 1.0%-1.5%.

• TZDs improve insulin action in peripheral tissues, particularly muscle.

• Both pioglitazone and rosiglitazone are indicated for combination therapy with sulfonylureas, metformin.

• Both LDL and HDL cholesterol concentrations may increase slightly.

• Rosiglitazone may increase cardiovascular events and is not recommended.

• When a thiazolidinedione is used, pioglitazone is preferred due to concerns about rosiglitazone cardiovascular safety in observational analysis.

SAFETY

• Thiazolidinediones are contraindicated in patients with known hypersensitivity. Their use in pregnancy and lactation is not recommended.

• TZDs alone, or in combination with other antidiabetic agents including insulin, can cause fluid retention, which may lead to heart failure. Do not use in patients with moderate to severe heart failure (NYHA Class III and IV cardiac status).

• Side effects may include moderate weight gain, edema and mild anemia, all due, at least in part, to fluid retention.

• As monotherapy, TZDs do not cause hypoglycemia.

• Measure ALT at baseline and periodically thereafter.

• Administration of gemfibrozil increases plasma levels of rosiglitazone. Decreases in the dose of rosiglitazone may be needed when gemfibrozil is added.

• Meta-analysis showed rosiglitazone may be associated with an increase in the risk of myocardial infarction and death from cardiovascular causes.

• Pioglitazone may not have the same cardiovascular concerns as rosiglitazone (Dormandy, 2005 [R])

• Macular edema has been reported in postmarketing experience in some diabetic patients who were taking thiazolidinedione.

• The risk of fracture should be considered in the care of patients, especially female patients, treated with thiazolidinedione.

• Physicians and patients should have an informed discussion around the risks of rosiglitazone.

Source: Compiled from pdr.net and FDA Warning 11/19/2007.



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Combination Products

Combination type

Fixed dose combination (mg)

Usual start dose (mg) Maximum dose per day

Cost

Sulfonylurea + metformin

Glipizide/metformin

2.5/250, 2.5/500, 5/500

As initial treatment:

2.5/250 daily

As second-line treatment:

2.5/500 or 5/500 twice daily

As initial treatment: 10 mg/2,000 mg

As second-line treatment: 20 mg/2,000 mg

$$

Sulfonylurea + metformin

Glyburide/metformin

1.25/250, 2.5/500, 5/500

As initial treatment:

1.25/250 daily or twice daily

As second-line treatment:

2.5/500 or 5/500 twice daily

20 mg/2,000 mg

$$

TZD + metformin

Pioglitazone/ metformin

15/500, 15/850

Not recommended as initial treatment; one tab PO daily or twice daily if on metformin monotherapy; 15 mg/500 mg by mouth twice daily or 15 mg/850 mg by mouth daily if on pioglitazone monotherapy

45 mg/ 2,550 mg/day

$$$$

TZD + metformin

Rosiglitazone/ metformin 1/500, 2/500, 4/500, 2/1,000, 4/1,000

Not recommended as initial treatment

8 mg/2,000 mg $$$$

TZD + sulfonylureas

Pioglitazone/glimerpiride 30/2, 30/4

Not recommended as initial treatment; 30/2 or 30/4 by mouth daily

45 mg/ 8 mg/day

$$$$$

TZD + sulfonylureas

Rosiglitzone/ glimerpiride

4/1, 4/2, 4/4

Not recommended as initial treatment; 4/1 or 4/2 by mouth daily

8 mg/4 mg/day

$$$$$

DDP-IV inhibitor + metformin

Sitaglipton/metformin 50/500, 50/1,000

As adjunct for patients in adequately controlled on metformin monotherapy: 50 mg sitaglipton plus current dose of metformin twice daily

100 mg/2,000 mg/day

$$$$$


25. Intensify TherapyIf treatment goals are not met on oral agents, or if oral agents are contraindicated, then it is necessary to begin insulin either alone or as an adjunct to oral therapy. There are many regimens that have been studied and are efficacious (Aviles-Santa, 1999 [A]; Relimpio, 1998 [A]; Yki-Järvinen, 1999 [A]; Zimmerman, 1998 [R]). The following are some commonly used regimens.



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Insulin as an adjunct to oral therapy:

• A once-daily (often at bedtime) dose of NPH, detemir or glargine insulin is added to metformin or thiazolidinediones. The recommended starting dose of basal insulin is often 0.1 U/kg, based on body weight. The basal insulin should be increased by two units every three days that blood glucoses in the a.m. remain above target. While adusting the basal insulin dose, the blood glucose should be monitored twice daily to three times daily to monitor glucose values and prevent hypoglycemic episodes. If patient is also on a sulfonylurea, it may be discontinued or reduced when insulin is added.

• A once-daily (often at bedtime) dose of insulin (as above) is added to sulfonylurea. The dose of the sulfonylurea may be reduced (approximately 50%) when insulin is added. The basal insulin should be increased by two units every three days that blood glucoses in the a.m. remain above target. While adjusting the basal insulin dose, the blood glucose should be monitored twice daily to three times daily to monitor glucose values and prevent hypoglycemic episodes. It must be noted that glargine or detemir may be dosed in the a.m. or p.m. Morning dosing may prevent nighttime hypoglycemic episodes and may also provide for improved blood glucose control.

Insulin alone:

• Twice-daily insulin regimen is established with progression to increased frequency of insulin administration as necessary to achieve treatment goals or to add flexibility to a patient's meal and activity schedules. Multiple dose insulin with rapid-acting and basal insulin therapy may offer patients with active lifestyles the greatest flexibility.

• One method of starting multidose insulin is to use a total daily dose of .2-.4 units/kg and prescribe half the dose as glargine once a day (morning or bedtime) and the other half as rapid acting insulin with meals (split appropriately according to the patient's frequency and pattern of meal sizes and/or carbohydrate consumption).

Oral agents as an adjunct to insulin therapy:

• Metformin may be helpful as an adjunct for patients who require large doses of insulin (e.g., greater than 100 units/day).

Blood Pressure Control Algorithm Annotations

26. Blood Pressure Control AlgorthimControl of blood pressure is at least as important as glycemic control for people with type 2 diabetes in reducing the risk of complications (Alder, 2000 [B]; Estacio, 2000 [A]).

SHEP, Syst-Eur and HOT trials all showed a greater absolute benefit from antihypertensive therapy in people with diabetes than in hypertensive people without diabetes (Hansson, 1998 [A]; SHEP Cooperative Research Group, 1991 [A]; Tuomilehto, 1999 [A]).

27. Is Systolic Blood Pressure Greater Than or Equal to 130 mmHg?For patients with type 2 diabetes mellitus, the systolic blood pressure goal is less than 130 mmHg and the diastolic blood pressure goal is less than 80 mmHg [Conclusion Grade II: See Conclusion Grading Work-sheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)] (Hansson, 1998 [A]; United Kingdom Prospective Diabetes Study [A], 1998c; UK Prospective Diabetes Study, 1998e [A]).



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A report from the UK Prospective Diabetes Study Group study showed an inverse relationship between systolic blood pressure and the aggregate end point for any complication related to diabetes (United Kingdom Prospective Diabetes Study Group (UKPDS), 1998e [R]. The lowest risk occurred at a systolic blood pres-sure below 120 mmHg.

The goal for patients with renal insufficiency and urinary protein excretion greater than 1-2 g/day should be less than 120/75 mmHg (American Diabetes Association, 2004c [R]).

28. Treat Systolic Blood Pressure to Less Than 130 mmHg. While ACE Inhibitors and ARBs Are Preferred First-Line Therapy, Two or More Agents (to Include Thiazide Diuretics) May Be RequiredNon-pharmacologic and pharmacologic methods are recommended at blood pressures greater than or equal to 130/80 mmHg. The initial focus of treatment should be the systolic blood pressure.

For patients with type 2 diabetes mellitus, ACE inhibitors or ARBs can reduce progression of micro- and macrovascular complications. [Conclusion Grade I: See Conclusion Grading Worksheet F – Annotations #28, 36 (Treatment with ACE Inhibitors or ARBs)] (HOPE Investigators, 2000a [A]; Lewis, 2001 [A]).

While ACE inhibitors and ARBs are preferred first-line therapy, two or more agents (to include thiazide diuretics) may be required. For patients with type 2 diabetes mellitus, thiazide diuretics in the treatment of hypertension can reduce cardiovascular events, particularly heart failure. [Conclusion Grade I: See Conclu-sion Grading Worksheet G – Annotations #28, 36 (Thiazide Diuretics)] (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002 [A]; Wing, 2003 [B]). The possible advantages to ACE inhibitors include renal protection, decreased insulin resistance, lack of adverse effect on lipids, and decreased cardiovascular risk.

In ALLHAT, chlorthalidone, at doses of 12.5 to 25 mg daily, was superior to other treatments at reducing cardiovascular events in both diabetic and non-diabetic patients.

Treatment of isolated systolic hypertension, as well as combined systolic and diastolic hypertension, in both young and elderly people protects against major cardiovascular diseases. Drug treatment should be initiated if systolic blood pressure is greater than or equal to 130 mmHg (Bakris, 2000 [R]).

Thiazide diuretics used in the treatment of hypertension can reduce cardiovascular events, especially heart failure, for patients with type 2 diabetes (Alkaharouf, 1993 [D]; American Diabetes Association, 2007c [R]; Chobanian, 2003 [R]; HOPE Investigators, 2000a [A]; Lewis, 1993 [A]).

29. Is Diastolic Blood Pressure Less Than 80 mmHg?For patients with type 2 diabetes mellitus, the systolic blood pressure goal is less than 130 mmHg and the diastolic blood pressure goal is less than 80 mmHg [Conclusion Grade II: See Conclusion Grading Work-sheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)] (Hansson, 1998 [A]; United Kingdom Prospective Diabetes Study [UKPDS] Group, 1998c [A]; United Kingdom Prospective Diabetes Study [UKPDS] Group, 1998e [A]).

The HOT trial provides evidence that a target diastolic blood pressure less than 80 mmHg has a cardioprotective effect in people with diabetes. This study reported that in the diabetic subgroup (n=1,501) major cardiovascular events were reduced by greater than 51% (p=0.005) in those randomized to a diastolic blood pressure goal of less than 80 mmHg compared to less than 90 mmHg. The HOT study has been criticized by some because this was a post hoc analysis of a subgroup of patients in the study and the number of events is relatively small. Nevertheless, results are consistent with United Kingdom Prospective Diabetes Study. United Kingdom Prospective Diabetes Study achieved an average diastolic blood pressure of 82 mmHg in the tightly controlled



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group (vs. 87 mmHg in the less tightly controlled group). The more tightly controlled group had diabetes related end points reduced by 24% (p=0.005) and death by 32% (p=.019) (United Kingdom Prospective Diabetes Study Group, 1998b [A]).

31. Treat Diastolic Blood Pressure to Less Than 80 mmHgCombinations of medications are often required to achieve goals. Thirty percent of patients in the tight blood pressure arm of the United Kingdom Prospective Diabetes Study with goal less than 150/85 mmHg required three or more antihypertensive medications to achieve the mean 144/82 mmHg. Findings from the ALLHAT study suggest that thiazide diuretics be considered as part of a multidrug regimen (United Kingdom Prospecitve Diabetes Study [UKPDS] Group, 1998a [M]; ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002 [A]).

Ongoing Management Algorithm Annotations

33. Ongoing Management and Follow-Up of People with DiabetesIn studies of general population groups, coronary artery disease deaths have been substantially reduced by the treatment of hypertension, hypercholesterolemia and smoking. Lipid treatment has also been shown to be of benefit in diabetes. Therefore, risk factor reduction is prudent for patients with diabetes (American Diabetes Association, 2007c [R]; Hansson, 1998 [A]).

• Frequency of visits depends on blood glucose control, changes in the treatment regimen, and presence of complications of diabetes or other medical conditions.

• Patients starting or having a major change in their treatment program (such as initiating insulin therapy) may need to be in contact with their care provider as often as daily until glucose control is achieved, the risk of hypoglycemia is low, and the patient is competent to conduct the treatment program.

• Contact with the patient after a major modification of the treatment plan (such as introducing a new medication) should not be delayed greater than one week.

• Regular visits should be scheduled for insulin-treated patients at least quarterly and for other patients at least semiannually. More frequent visits may be necessary if treatment goals are not achieved.

• Cardiovascular disease is the primary cause of morbidity and mortality in people with type 2 diabetes. The risk of coronary artery disease is approximately doubled in men and quadrupled in women with diabetes.

• At each encounter, ask if the patient has experienced symptoms of hypoglycemia or low blood glucose, and educate the patient on appropriate recognition, prevention and management.

• If the patient has a history of severe hypoglycemia (assistance of another person was needed to treat a low glucose) or has developed hypoglycemia unawareness, evaluate the treatment goals for appropriate safety.

34. Maintain Treatment Goals• Nutrition/physical activity: work with individual patients regularly to set realistic goals.

• Monitor A1c every three to six months. In insulin-treated patients and non-insulin-treated patients with poor metabolic control, quarterly A1c may assist management.

- Review blood glucose at all patient encounters. Reinforce blood glucose targets with patients and educate regarding hypoglycemia.



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• Monitor lipid profile yearly (total cholesterol, triglycerides, high-density lipoprotein-cholesterol and low-density lipoprotein-cholesterol): treat to achieve recommended goals (see Annotation #13, "Treat-ment Goals for Patients Without Cardiovascular Disease"). If lipid goals are consistently met, patient is in metabolic control, has stable clinical conditions, and has not had a change in medication, an annual lipid profile is not mandatory.

Diabetes is a major risk factor for coronary artery disease, and many patients with diabetes also have lipid disorders (American Diabetes Association, 2004a [R]). Thus, control of dyslipidemia in diabetes is important because evidence shows that correcting lipid disorders reduces the rate of coronary artery disease events.

• Monitor blood pressure each visit and control hypertension to recommended levels. See the Blood Pressure Control algorithm.

• Ask about aspirin use and recommend aspirin use in patients age 40 and over unless contraindicated (American Diabetes Association, 2007c [R]).

• Ask about alcohol and tobacco use and assist with cessation if indicated.

35. Annual Assessment of ComplicationsTargeted Annual History and Physical Exam • The history should assess (American Diabetes Association, 2007c [R]):

- Results of self-monitoring blood glucose – validate results at least once a year (e.g., check patient's glucose meter against an office random capillary glucose)

- Adjustments by the patient of the therapeutic regimen

- Frequency, causes and severity of both hyperglycemia and hypoglycemia

- Problems with adherence to therapeutic regimen

- Symptoms suggesting development or progression of the complications of diabetes

- Current prescribed medications, over-the-counter medications, dietary supplements and alternative therapies

- Documentation of eye care specialist exam results

- Alcohol/drug use patterns

• Assess for symptoms of depression

- Lab assessment of liver function and/or creatinine to assess ongoing acceptability of medication usage

• The targeted physical exam should assess:

- Weight, body mass index

- Blood pressure

- Cardiovascular – evaluation of preexisting problems

- Feet (nails, web spaces, calluses, ulcers, structural deformities, protective sensation and shoes)



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Specialist Dilated Eye ExamA dilated eye examination for diabetic eye disease performed by an ophthalomologist or optomostrist is recommended annually for patients with type 2 diabetes mellitus (American Diabetes Association, 2007c [R]). Less frequent exams (every two to three years) may be considered in the setting of a normal eye exam.

Renal AssessmentUrinary albumin excretion should be tested annually by a microalbuminuria method. There are racial/ethnic variability with regard to the prevalence of end-stage renal disease with Native Americans, Latinos (especially Mexican Americans), and African Americans having higher rates than non-Hispanic whites with type 2 diabetes (American Diabetes Association, 2004d [R]). If albuminuria is above normal, serum creati-nine should be measured. Screening for microalbuminuria can be performed by three methods (American Diabetes Association, 2004d [R]; Nelson, 1991 [B]; Bennett, 1995 [R]):

• Measurement of the albumin-to-creatinine ratio in a random, spot collection. This is easiest to perform, generally accurate and therefore is the preferred screening method.

• 24-hour collection with creatinine, allowing for simultaneous measurement of creatinine clear-ance

• Timed (four-hour or overnight) collection

Some factors can artificially increase the levels of albumin in the urine and should be avoided at the time of the urine collection; these factors include blood in the urine, prolonged heavy exercise, fever, congestive heart failure, uncontrolled diabetes, severe hypertension, urinary tract infection and vaginal fluid contami-nation of specimen.

If the dipstick or urine analysis test is negative for protein, then a more sensitive early screening test is indicated. A qualitative urinary microalbumin screen can be used to detect urinary microalbumin. If the qualitative test is positive, a quantitative test must be performed.

A microalbumin screening test should be done each year on patients with type 2 diabetes. If positive (exceeds 30 mg/gm), it should be repeated twice in the next three months.

If two out of three of these screening microalbuminuria tests are positive, the individual has microalbuminuria, and interventions should be considered. A negative finding should be followed annually; a positive finding should be followed periodically to see if the interventions are effective in diminishing the albuminuria (Bennett, 1995 [R]; Hannah, 1999 [R]; Mogensen, 1996 [R]; National Institutes of Health, 1993 [R]).

See Appendix A, "Treatment of Diabetic Nephropathy."

Comprehensive Foot Exam with Risk Assessment Patients with one or more risk factors for foot complications should be educated about their risk factors and appropriate measures taken to avoid complications. Measures may include self-management education, more intensive follow-up, and/or referral to appropriate specialist (American Diabetes Association, 2007c [R]; Mayfield, 1998 [R]).

Risk factors for foot complications include:

• Loss of protective sensation. Protective sensation can be assessed using either a 5.07 Semmes-Weinstein monofilament for light touch or by testing vibration using a 128-Hz tuning fork at the dorsum of the interphalangeal joint of the great toe, or both. Patients with reduced or absent sensa-tion with either of these tests should be educated about their risk and the need for proper foot care to prevent foot complications. See Appendix B, "Using a Semmes-Weinstein Monofilament to Screen the Diabetic Foot for Peripheral Sensory Neuropathy."



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• Peripheral vascular disease (absent pedal pulse, history of claudication or ischemic skin changes)

• Structural deformities (bunion, hammertoes, Charcot deformity, limited joint mobility or prior amputation)

• Skin disorders (nail deformity, callus, fissure, tinea or ulceration)

• Footwear (excessively worn, ill-fitting or inappropriate shoes)

Cardiovascular and Cerebrovascular Complication Assessment• History of cardiovascular symptoms such as chest pain, vascular claudication, TIA

• Cardiac and carotid exams

• Evaluate cardiovascular status before advising increased intensity of exercise (American Diabetes Association, 2004e [R]; Sigal, 2004 [R]).

Special Considerations • Influenza vaccine every year

• Pneumococcal vaccine – consider repeating the immunization for those at risk of losing immunity after five years including:

- Nephrotic syndrome

- Chronic renal disease

- Other immunocompromised states

• There is evidence that ACE inhibitors and ARBs are beneficial in reducing cardiovascular morbidity and mortality in acute MI, congestive heart failure and type 2 diabetes patients at high risk for cardio-vascular disease; they are also beneficial in improving renal outcomes in diabetes. Results of the HOPE (Heart Outcomes Prevention Evaluation) study strongly support the use of ACE inhibitors for patients with diabetes who are at high risk for cardiovascular disease. In the Second Australian National Blood Pressure Study (ANblood pressure2), the use of ACE inhibitors in older patients was associated with better cardiovascular outcomes, despite similar reductions in blood pressure from diuretics. Confirming studies would be helpful to strengthen this recommendation or to generalize recommendations to all patients with diabetes (HOPE Investigators [A], 2000a; Wing, 2003 [A]).

• Vitamin E has no apparent effect on cardiovascular outcomes (HOPE Investigators, 2000b [A]).

• Osteoporosis: Type 2 diabetes does not appear to be a risk factor for decreased bone mineral density; nonetheless, some studies have found an increased fracture risk for people with type 2 diabetes (Schwartz, 2001 [B]). Hypoglycemic episodes, decreased visual acuity secondary to retinopathy, and altered balance and postural control secondary to peripheral and autonomic neuropathy can all increase the risk of falls and fracture.

In the absence of diabetes specific osteoporosis screening guidelines, it is reasonable to follow general osteoporosis screening recommendations for people with diabetes. See the ICSI Diagnosis and Treat-ment of Osteoporosis guideline for more information.



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36. Treatment and Referral for ComplicationsNephropathy

In type 2 diabetes, albuminuria may be present at the time of diagnosis in about 10% of patients, and another 10% later develop it. Progression to renal failure is less certain in type 2 patients than in type 1 patients and appears to be modulated by genetic and other factors.

Patients with clinical nephropathy almost always have retinopathy and coronary artery disease.

Numerous interventions are appropriate at different stages of renal function in order to prevent or slow the progression of renal disease and associated cardiovascular disease and include (American Diabetes Asso-ciation, 2004d [R]:

• Glucose Control – Improved glucose control at any stage of renal function reduces renal disease progression. See the Glycemic Control algorithm.

• For patients with type 2 diabetes mellitus, ACE inhibitors or ARBs can reduce progression of micro- and macrovascular complications. [Conclusion Grade I: See Conclusion Grading Worksheet F – Annotations #28, 36 (Treatment with ACE Inhibitors or ARBs)] (HOPE Investigators, 2000a [A]; Lewis, 2001 [A]). These agents appear effective even in normotensive microalbuminuric indi-viduals. This class of drugs must not be used in pregnancy. Within one week of initiation, check for elevations in potassium and creatinine levels and monitor for cough.

• Hypertension Control – Although ACE inhibitors and ARBs seem to have special renal protective properties beyond their antihypertensive effect, any effort to optimize blood pressure will help the kidneys. When significant microalbumin or overt nephropathy are present, there may be a tendency to retain sodium. In this case, a loop diuretic added to the antihypertensive regimen is often helpful. A goal blood pressure of less than 130/80 mmHg is recommended (American Diabetes Association, 2007c [R]). See the Blood Pressure Control algorithm.

For patients with type 2 diabetes, thiazide diuretics in the treatment of hypertension can reduce cardiovascular events, particularly heart failure. [Conclusion Grade I: See Conclusion Grading Worksheet G – Annotations #28, 36 (Thiazide Diuretics)] (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002 [A]; Wing, 2003 [B]).

In ALLHAT, chlorthalidone, at doses of 12.5-25 mg daily, was superior to other treatments at reducing cardiovascular events in both diabetic and non-diabetic patients.

• Cardiovascular Risk Factor Intervention – Dyslipidemia is often present with microalbuminuria and should be treated aggressively. Dyslipidemia may be an independent risk factor for progression of renal disease. Smoking is associated with the onset and progression of microalbuminuria.

• Restriction of dietary protein has been shown to slow progression of overt nephropathy (macroalbu-minuria), and there may be some benefit in dietary protein reduction in microalbuminuric patients. In these circumstances, protein intake should be reduced to the adult recommended daily allowance of 0.8-1.0 g/kg body weight per day with microalbuminuria present, and 0.8 gm/kg body weight per day with macroalbuminuria present (American Diabetes Association, 2007b [R]).

Treatment for microalbuminuria includes aggressive blood pressure control, glycemic control, ACE inhibitor or ARB use, and aggressive cardiovascular risk factor screening and management. Strongly consider referral to nephrology any patients with a creatinine greater than 1.5 mg, or nephrotic range proteinuria (greater than 3 gm/24 hour). Nephrology interventions often include early patient education as renal disease progresses, review and reinforcement of the medical regimen, and preservation of arm veins for future vascular access. Patients with a creatinine clearance of less than 30 mL/min should be referred to nephrology for discussions of future options and to enhance



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the ability to receive a future transplant. These patients also have significant enough renal impair-ment that they also benefit from more intensive nutritional interventions and proper management of anemia and bone disease (American Diabetes Association, 2004d [R]; DeFronza, 1995 [R]; HOPE Investigators, 2000a [A]; Karter, 2002 [B]; Lewis, 1993 [A]; Lewis, 2001 [A]; Ravid, 1993 [A]; Viberti, 1994 [A]).

Neuropathy – Peripheral neuropathy is difficult to prevent and treat. Most patients with type 2 diabetes and peripheral neuropathy have few symptoms but are found on examination to have diminished reflexes and sensation. Sometimes neuropathy can be very painful, especially at night, with "pins-and-needles" numb-ness and tingling in a stocking-and-glove distribution. Absence of reflexes or decreased thermal, vibratory, proprioceptive or pain sensation may be noted on examination and confirm the diagnosis. Good glycemic control should be the first control to symptomatic neuropathy. Treatment with amitriptyline, nortriptyline or trazodone in doses beginning at 25 mg at night and increasing to 75 mg may help some patients. Topical treatment with capsaicin, 0.025% cream three to four times per day, has also shown benefit. Carbamazepine, duloxetine and gabapentin may also improve neuropathic pain. These medications may provide symptomatic relief, but they do not improve the neuropathy (Boulton, 2005 [R]).

Retinopathy – Prevalence of retinopathy is related to the duration of diabetes mellitus. After 20 years of type 2 diabetes mellitus, more than 60% of patients have some degree of retinopathy (Fong, 2004 [R]). Diabetic retinopathy is estimated to be the most frequent cause of new cases of blindness among adults ages 20 to 74 years.

Up to 21% of patients with type 2 diabetes mellitus are found to have retinopathy at the time of diagnosis of diabetes mellitus (Fong, 2004 [R]). Generally retinopathy progresses from mild background abnormalities to preproliferative retinopathy to proliferative retinopathy.

Poor glucose control is associated with progression of retinopathy. High blood pressure is a risk factor for the development of macular edema and is associated with the development of proliferative retinopathy (Fong, 2004 [R]).

Screening for diabetic retinopathy saves vision at a relatively low cost. In fact, screening costs may be less than the costs of disability payments for those who become blind. Laser photocoagulation surgery is effective in preventing visual loss in diabetic retinopathy.

Studies have shown that retinal examinations by physicians who are not eye care specialists are not reliable in detecting retinopathy (American College of Physicians, American Diabetes Association, and American Academy of Ophthalmology, 1992 [R]; Diabetic Retinopathy Study Research Group, The, 1981 [R]; ETDRS Research Group, 1985 [A]; ETDRS Research Group, 1991 [A]; Fong, 2004 [R]; Klein, 1984 [C]; Klein, 1987 [R]).

Treatment includes glycemic and blood pressure control. Periodic screening and dilated eye exams by an eye specialist and early treatment of diabetic retinopathy prevents visual loss (Fong, 2004 [R]). See the Glycemic Control and Blood Pressure Control algorithms.

Cardiovascular and cerebrovascular disease – Treatment includes control of cardiovascular risk factors (hypertension, hyperlipidemia and smoking cessation) and aspirin use. Consider referring patients with known coronary artery disease to cardiology and patients with known carotid disease to surgery.

Heart failure is also common in patients with diabetes. Caution should be used when prescribing spironolac-tone and eplerenone to people with diabetes, especially in combination with ACE inhibitors.

Close monitoring of potassium and renal function is necessary. Thiazolidinediones must also be used with caution in patients with Class I and II congestive heart failure or patients at high risk for congestive heart failure. Close monitoring for fluid retention and signs of congestive heart failure is needed. Thiazolidin-ediones should not be used in Class III and IV congestive heart failure.



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For patients with type 2 diabetes mellitus, thiazide diuretics in the treatment of hypertension can reduce cardiovascular events, particularly heart failure. [Conclusion Grade I: See Conclusion Grading Worksheet G – Annotations #29, 36 (Thiazide Diuretics)] (ALLHAT Officers and Coordinators for the ALLHAT Collab-orative Research Group, The, 2002 [A]; Wing, 2003 [A])

Patients with type 2 diabetes have twice the average risk of suffering a stroke (American Diabetes Asso-ciation, 1998 [R]). It is unclear whether good glycemic control reduces this risk. However, treatment of hypertension, smoking and hyperlipidemia reduces the risk of stroke in most persons. See Annotation #14, "Treatment Goals for Patients With Cardiovascular Disease," and the Blood Pressure Control algorithm.

Peripheral vascular disease – Peripheral arterial disease is commonly associated with diabetes (American Diabetes Association, 2007c [R]). As many as 36% of patients with diabetes have lower-extremity peripheral arterial disease based on lower-extremity blood pressure readings. However, a typical history of intermittent claudication or an absent peripheral pulse is less commonly noted.

Peripheral vascular disease in combination with peripheral neuropathy places patients with diabetes at increased risk for non-traumatic amputations of the lower extremity. Peripheral vascular disease may be slowed by smoking cessation and treatment of hypertension and dyslipidemia. See Annotation #14, "Treat-ment Goals for Patients With Cardiovascular Disease," and the Blood Pressure Control algorithm.

Aggressive daily foot care, inspection of the feet at every office visit, early treatment of foot infections, treat-ment of callus, use of moisturizing lotion and proper footwear may forestall problems, including amputation. Vascular surgery may also prevent amputation in some patients with established severe peripheral vascular disease (American Diabetes Association, 2004f [R]).

Proper high-risk foot management is necessary to prevent ulceration and amputation. Consider referral of patients with claudication and/or absent pedal pulses to surgery. See the Glycemic Control and Blood Pressure Control algorithms.



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Appendix A – Treatment of Diabetic Nephropathy


Screen patients with diabetic nephropathy

B1

Dipstick test urine sample• Positive microablumin reaction

B2

Semiquantitative immunoassaytest• Positive correlates well with > 20 mg albumin/24 hr

B3

Quantitative tests• Albumin/creatinine ratio on random urine sample (easiest for patients)• 24-hour urine collection• Time urine collection (4-hour or overnight)• Positive is > 30 mg/24 hr or 30 > mg/g Cr

B4

Positive for microalbumin?

B5

Repeat screen annually

B6

no

Verify all positive tests• Use 2 additional quantitative screening tests• Perform verification tests over next 2-3 months

B7

yes

False positives for urinealbumin may occur secondaryto:• UTI• Fever• Blood in urine• Heart failure• Extreme hypertension• Vaginal fluid contamination• Uncontrolled blood glucose• Prolonged exercise

B5

2 of 3 tests positive for urine

albumin?

B8

no

Definition for microalbuminuriaand macroalbuminuria• Microalbuminuria: > 30 mg/ 24 hr or > 30 mg/g Cr• Macroalbuminuria: > 300 mg/ 24 hr or > 300 mg/g Cr

Macroalbuminuria: Suspect overt nephropathy• Referral to nephrology specialist

B8

Microalbuminuria: Perform periodic 24-hr creatinine clearance and urine protein tests to assess renal function and treatment success• Blood pressure control• ACE inhibitor use• Glycemic control• Lipid/CV risk factor control• Consider referral to nephrology specialist

yes

B9 B10


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Appendix B – Using a Semmes-Weinstein Monofilament to Screen the Diabetic Foot for Peripheral Sensory Neuropathy


1) Show the monofilament to the patient and touch it to his/her arm to demonstrate that it does not hurt.2) Use the Semmes-Weinstein 5.07/10 gram monofilament to test sensation at the indicated sites on each foot*.

Avoid applying the monofilament to calluses, ulcers, or scars. A foot exam is not reimbursed my Medicare without monofilament sensation testing in four locations.

3) Hold the monofilament perpendicular to the skin and touch it to the skin using a smooth motion with sufficient force to cause the filament to bend. The test should take about 1-1/2 seconds at each site.

4) Ask the patient to respond "yes" when the filament is felt. If the patient does not respond when you touch a given site on the foot, continue on to another site in a random sequence. When you have completed testing all sites on the foot, retest any site(s) where the patient did not feel the filament.

5) The results of the monofilament testing should be documented in the medical record**. PATIENTS WHO CANNOT FEEL THE MONOFILAMENT AT ANY SITE SHOULD BE CONSIDERED TO BE INSENSATE AND AT INCREASED RISK FOR ULCERATION AND AMPUTATION.

*Testing at the first and fifth metatarsal heads is sufficient. This combination of sites has been shown to detect the insensate foot with reasonable sensitivity (80%) and specificity (86%). Testing the great toes may be of added benefit.**Chart documentation is required for the American Diabetes Association – Provider Recognition Program. An annual diabetic foot examination is also one of the eight diabetes quality improvement project (DQIP) measures adopted by the National Committee for Quality Assurance (NCQA) and the Health Care Financing Administration.

58Copyright © 2009 by Institute for Clinical Systems Improvement

Released in May 2009 for Thirteenth Edition. The next scheduled revision will occur within 12 months.

Contact ICSI at: 8009 34th Avenue South, Suite 1200; Bloomington, MN 55425; (952) 814-7060; (952) 858-9675 (fax)

Online at http://www.ICSI.org


Document Drafted Nov 1994 – Apr 1995

First Edition Mar 1996

Second Edition Apr 1997

Third Edition May 1998

Fourth Edition Apr 1999

Fifth Edition Apr 2000

Sixth Edition Oct 2001

Seventh Edition Oct 2002

Eighth Edition Dec 2003

Ninth Edition Dec 2004

Tenth Edition Dec 2005

Eleventh Edition Dec 2006

Twelfth Edition Apr 2008

Thirteenth Edition Begins June 2009

Supporting Evidence:


Original Work Group MembersJanet Davidson, RN, CDENurse ClinicianPark Nicollet ClinicJinnet Fowles, PhDMeasurement AdvisorInstitute for Research and Education HealthSystem MinnesotaMarion Franz, RD, CDEDieteticsInternational Diabetes CenterPatrick O'Connor, MDFamily PracticeHealthPartnersTeresa Pearson, MS, RN, CDEHealth EducationHealthPartners

Greg Angstman, MDFamily Practice, Work Group LeaderMayo ClinicRichard Bergenstal, MDEndocrinologyInternational Diabetes CenterMary BergeneBHCAG RepresentativeHoneywell, Inc.Don Bishop, PhDMinnesota Department of Health RepresentativesMinnesota Dept. of HealthCindy Clark, MSMinnesota Department of Health RepresentativesMinnesota Dept. of Health

Peg Sannes, R PhPharmacyHealthPartnersMary Shelerud, RNFacilitatorMayo ClinicDace Trence, MDEndocrinologyHealthPartnersBruce Zimmerman, MDEndocrinologyMayo Clinic


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Brief Description of Evidence Grading

Individual research reports are assigned a letter indicating the class of report based on design type: A, B, C, D, M, R, X.

A full explanation of these designators is found in the Foreword of the guideline.

II. CONCLUSION GRADES

Key conclusions (as determined by the work group) are supported by a conclusion grading worksheet that summarizes the important studies pertaining to the conclusion. Individual studies are classed according to the system defined in the Foreword and are assigned a designator of +, -, or ø to reflect the study quality. Conclusion grades are determined by the work group based on the following definitions:

Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.

Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.

Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results from different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.

Grade Not Assignable: There is no evidence available that directly supports or refutes the conclusion.

The symbols +, –, ø, and N/A found on the conclusion grading worksheets are used to designate the quality of the primary research reports and systematic reviews:

+ indicates that the report or review has clearly addressed issues of inclusion/exclusion, bias, generaliz-ability, and data collection and analysis;

– indicates that these issues have not been adequately addressed;

ø indicates that the report or review is neither exceptionally strong or exceptionally weak;

N/A indicates that the report is not a primary reference or a systematic review and therefore the quality has not been assessed.



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Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antago-nist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60. (Class A)

Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing diabetes prevention study: a 20-year follow-up study. Lancet 2008;371:1783-89. (Class A)

Lindström J, Ilanne-Parikka P, Peltonen M, et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish diabetes prevention study. Lancet 2006;368:1673-79. (Class A)

Lorig KR, Ritter P, Stewart AL, et al. Chronic disease self-management program: 2-year health status and health care utilization outcomes. Med Care 2001;39:1217-23. (Class D)

Lustman PJ, Gavard JA. Psychosocial aspects of diabetes in adult populations. In Diabetes in America, 2nd Ed. 507-18. On-line reference, accessed July, 2001 at http://diabetes-in-america.s-3.com/ (Class R)

Malmström RE, Settergren M, Böhm F, et al. No effect of lipid lowering on platelet activity in patients with coronary artery disease and type 2 diabetes or impaired glucose tolerance. Thromb Haemost 2009;101:157-64. (Class A)

Mayfield JA, Reiber GE, Sanders LJ, et al. Preventive foot care in people with diabetes. Diabetes Care 1998;21:2161-77. (Class R)



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McFarlane SI. Diabetes prevention between RAAS inhibition and PPAR-gamma stimulation: the diabetes reduction assessment with ramipril and rosiglitazone medication (DREAM) trial. J Cardiometab Syndr 2007;2:149-50. (Class A)

Medical Letter® on Drugs and Therapeutics, The. Rosiglitazone for type 2 diabetes mellitus. 1999;41. (Class R)

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Morrish NJ, Stevens LK, Fuller JH, et al. Risk factors for macrovascular disease in diabetes mellitus: the London follow-up to the WHO multinational study of vascular disease in diabetes. Diabetologia 1991;34:590-94. (Class B)

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Nelson RG, Knowler WC, Pettitt DJ, et al. Assessment of risk of overt nephropathy in diabetic patients from albumin excretion in untimed urine specimens. Arch Intern Med 1991;151:1761-65. (Class B)

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O'Connor PJ, Sperl-Hillen JM, Johnson PE, et al. Advances in patient safety: clinical inertia and outpa-tient medical errors. AHRQ 2005a;2:293-308. (Class R)

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Pate RR, Pratt M, Blair SN, et al. Physical activity and public health: a recommendation from the Centers for Disease Control Prevention and the American College of Sports Medicine. JAMA 1995;273:402-07. (Class R)

Peters AL, Davidson MB. Maximal dose glyburide therapy in markedly symptomatic patients with type 2 diabetes: a new use for an old friend. J Clin Endocrinol Metab 1996;81:2423-27. (Class D)

Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing physi-cians' health study. N Engl J Med 1989;321:129-35. (Class A)

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Relimpio F, Pumar A, Losada F, et al. Adding metformin versus insulin dose increase in insulin-treated but poorly controlled type 2 diabetes mellitus: an open-label randomized trial. Diabet Med 1998;15:997-1002. (Class A)

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Sever PS, Poulter NR, Dahlöf B, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial – lipid-lowering arm (ASCOT-LLA). Diabetes Care 2005;28:1151-57. (Class A)

SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the systolic hypertension in the elderly program. JAMA 1991;265:3255-64. (Class A)

Shepard J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the treating to new targets (TNT) study. Diabetes Care 2006;29:1220-26. (Class A)

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Sirois C, Poirier P, Moisan J, Grégoire JP. The benefit of aspirin therapy in type 2 diabetes: what is the evidence? Int J Cardiol 2008;129:172-79. (Class M)

Solberg LI, Mosser G, McDonald S. The three faces of performance measurement: improvement, accountability, and research. Jt Comm J Qual Improv 1997;23:135-47 (Class R)

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Tuomilehto J, Lindstrom J, Eriksson JH, et al. Prevention of type 2 diabetes mellitus by changes in life-style among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50. (Class A)

Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677-84. (Class A)

Turner R, Cull C, Frighi V, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005-12. (Class A)

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UK Prospective Diabetes Study (UKPDS) Group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-12. (Class B)

UK Prospective Diabetes Study (UKPDS) Group. Cost effectiveness analysis of improved blood pres-sure control in hypertensive patients with type 2 diabetes. UKPDS 40. BMJ 1998a;317:720-26. (Class M)

UK Prospective Diabetes Study Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes mellitus (UKPDS 34). Lancet 1998b;352:854-64. (Class A)

UK Prospective Diabetes Study (UKPDS) Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998c;317:713-20. (Class A)

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998d;352:837-53. (Class A)

UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998e;317:703-20. (Class A)

Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002;87:978-82. (Class B)



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U.S. Department of Health and Human Services. In Treating Tobacco Use and Dependence. June 2000. (Class R)

van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67. (Class A)

Viberti G, Mogensen CE, Groop LC, et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA 1994;271:275-79. (Class A)

Vijan S, Hofer TP, Hayward RA. Estimated benefits of glycemic control in microvascular complications in type 2 diabetes. Ann Intern Med 1997;127:788-95. (Class D)

Walsh M, Spurling G. Aspirin in type 2 diabetes: is there any evidence base? BMJ 2008;337:1163-65. (Class R)

Wang C, Harris WS, Chung M, et al. n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review. Am J Clin Nutr 2006;84:5-17. (Class M)

Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583-92. (Class A)

Winkelmayer WC, Setoguchi S, Levin R, Solomon DH. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 2008;168:2368-75. (Class B)

Yki-Järvinen H, Ryysy L, Nikkilä K, et al. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. Ann Intern Med 1999;130:389-96. (Class A)

Zimmerman BR, Hagen MD. An evaluation of new agents in the treatment of type 2 diabetes. J Fam Pract 1998;47(Suppl 1):S37-S43. (Class R)



www.icsi.org

70

Conclusion Grading Worksheet A – Annotation #4 (Prediabetes)


Wo

rk

Gro

up

's C

on

clu

sio

n:

•

Lif

esty

le m

od

ific

atio

ns,

su

ch a

s n

utr

itio

n,

exer

cise

an

d e

ven

mo

des

t w

eig

ht

loss

, ar

e re

com

men

ded

fo

r

pre

ven

tio

n o

r d

elay

ed p

rog

ress

ion

of

pat

ien

ts w

ith

pre

dia

bet

es.

•

Ph

arm

aco

ther

apy

, su

ch a

s m

etfo

rmin

, ar

e ef

fect

ive

in s

om

e p

atie

nts

wit

h p

red

iab

etes

.

•

Th

ere

are

con

cern

s th

at t

he

rece

nt

mo

dif

icat

ion

of

the

def

init

ion

of

imp

aire

d f

asti

ng

glu

cose

by

th

e A

mer

ican

Dia

bet

es A

sso

ciat

ion

has

lo

w s

pec

ific

ity

an

d l

ow

po

siti

ve

pre

dic

tiv

e v

alu

e co

mp

are

d t

o t

he

WH

O d

efin

itio

n.

Co

nclu

sio

n G

ra

de:

II

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le S

ize

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

rati

o, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(ita

liciz

ed)

Bo

rch

-

Joh

nso

n,

et a

l.,

20

04

Ob

serv

a-

tio

nal

,

cro

ss-

sect

ion

al

stu

dy

D

+

Dat

a p

oo

led

fro

m 5

inte

rnati

on

al p

op

ula

tio

n b

ase

d

stu

die

s:

1)

Dan

ish

IN

TE

R9

9

(n=

62

65

ad

ult

s 3

0-

61

y)

DE

TE

CT

-2 S

tud

ies:

2)

Par

is

Pro

spect

ive(

n=

70

34

adu

lts

44

-55

y)

3)

Gin

gd

oa

(Ch

ina)

(n=

18

08

ad

ult

s 3

0-

74

y)

4)

NU

DS

(In

dia

)

(n=

10

03

9 a

du

lts

22

-99

y)

5)

NH

AN

ES

19

88

-

19

94

(n

=3

51

7

adu

lts

40

-74

y)

Pri

mar

y o

bje

cti

ve

was

to

ev

alu

ate

the c

on

seq

uen

ces

of

20

03

Am

eric

an D

iab

etes

Ass

ocia

tio

n e

xp

ert

com

mit

tee r

evis

ion

of

dia

gn

ost

ic c

rite

ria

for

imp

air

ed f

asti

ng

glu

cose

fro

m 6

.1 t

o 5

.6

mm

ol/

l; s

peci

fica

lly

wit

h r

egar

d t

o

1)

the

pre

vale

nce

of

imp

aire

d f

ast

ing

glu

cose

in

fiv

e

dif

fere

nt

cou

ntr

ies,

2)

the

con

cord

ance

betw

een

im

pair

ed f

ast

ing

glu

cose

stat

us

and

im

pair

ed g

luco

se t

ole

ran

ce,

and

3)

Th

e car

dio

vas

cula

r ri

sk p

rofi

le o

f th

ese

gro

up

s.

Th

e p

rop

ose

d c

han

ges

in

dia

gn

ost

ic c

rite

ria

wo

uld

in

cre

ase

the

pre

vale

nce

of

imp

air

ed f

ast

ing

glu

cose

in

Den

mark

fro

m 1

1.8

%

to 3

7.6

%, w

hic

h w

ou

ld i

den

tify

60

% o

f al

l su

bje

cts

wit

h

imp

aire

d g

luco

se t

ole

ran

ce

com

pare

d t

o 2

9.2

% w

ith

th

e o

ld

crit

eria

. H

ow

ever,

am

on

g i

nd

ivid

uals

wit

h t

he

new

im

pai

red

fast

ing

glu

cose

cat

ego

ry, 1

8.5

% w

ou

ld a

lso

hav

e im

pair

ed

glu

cose

to

lera

nce

; fu

rth

erm

ore

, in

div

idu

als

wit

h i

sola

ted

imp

aire

d f

asti

ng

glu

cose

had

lo

wer

insu

lin

lev

els

an

d a

lo

wer

card

iov

asc

ula

r d

isease

ris

k c

om

pare

d w

ith

cu

rren

t W

HO

cri

teri

a.

Dat

a fr

om

DE

TE

CT

-2 a

lso

sh

ow

ed a

n i

ncr

eas

e in

th

e p

rev

ale

nce

of

imp

aire

d f

ast

ing

glu

cose

– t

he

nu

mb

er o

f in

div

idu

als

ages

40-

64

yea

rs w

ith

im

pair

ed f

ast

ing

glu

cose

in

urb

an I

nd

ia, u

rban

Ch

ina,

an

d t

he

US

A w

ou

ld i

ncre

ase

by

78

%, 1

35

% a

nd

19

3%

,

resp

ect

ivel

y, w

ith

th

e n

ew

cri

teri

a co

mp

are

d t

o t

he

old

cri

teri

a.

Th

e au

tho

rs c

on

clu

de

that

a r

evis

ion

of

dia

gn

ost

ic c

rite

ria f

or

imp

aire

d

fast

ing

gly

cem

ia w

ill

incr

eas

e th

e

pre

vale

nce

of

imp

air

ed f

ast

ing

glu

cose

tw

o-

to f

ou

rfo

ld.

Im

pai

red

fast

ing

glu

cose

an

d i

mp

aire

d

glu

cose

to

lera

nce

wil

l re

main

tw

o

dif

fere

nt

cat

ego

ries

of

glu

cose

into

lera

nce.

T

he

new

im

pair

ed

fast

ing

glu

cose

gro

up

wil

l h

ave

a

mo

re f

avo

rab

le c

ard

iov

asc

ula

r ri

sk

pro

file

th

an t

he

gro

up

def

ined

by

WH

O,

and

th

e u

sefu

lness

of

imp

aire

d f

asti

ng

glu

cose

as

a t

arg

et

gro

up

fo

r d

iab

ete

s p

rev

enti

on

may

bec

om

e q

uest

ion

able

.

New

Thi

rteen

th E

ditio

n, M

ay 2

009.


www.icsi.org

71

Conclusion Grading Worksheet A – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #4 (Prediabetes) Thirteenth Edition/May 2009

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-

val

ue,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s

rati

o,

lik

elih

oo

d r

atio

, n

um

ber

nee

ded

to

tre

at)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Tw

igg

,

et a

l.,

20

07

Po

siti

on

Sta

tem

ent

bas

ed o

n a

syst

emat

ic

rev

iew

of

lite

ratu

re f

rom

the

Au

stra

lian

Dia

bet

es

So

ciety

an

d

Au

stra

lian

Dia

bet

es

Ed

uca

tors

Ass

oci

atio

n

R

+

A r

evie

w o

f p

eer-

rev

iew

ed j

ou

rnal

s

was

co

nd

uct

ed

usi

ng

ME

DL

INE

19

66

-20

05

).

Sea

rch

term

s

incl

ud

ed

pre

dia

bet

es,

glu

cose

into

lera

nce,

IG

T,

IFG

, im

pair

ed

glu

cose

to

lera

nce

,

imp

aire

d f

asti

ng

glu

cose

an

d

imp

aire

d f

asti

ng

gly

cem

ia.

Art

icle

s w

ere

gra

ded

acc

ord

ing

to l

evel

of

evid

ence

.

-Th

e ai

m o

f th

is r

epo

rt w

as t

o d

evel

op

reco

mm

end

atio

ns

for

the

clin

ical

man

agem

ent

of

pre

dia

bet

es

for

ph

ysi

cia

ns

and

all

ied

heal

th c

are

pro

fess

ion

als.

- P

red

iab

etes

is d

efin

ed a

s th

e p

rese

nce

of

imp

air

ed

fast

ing

glu

cose

/gly

cem

ia a

nd

/or

imp

air

ed g

luco

se

tole

ran

ce.

- P

red

iab

etes

affe

cts

abo

ut

16

.4%

of

Au

stra

lian

ad

ult

s.

- P

eop

le w

ith

pre

dia

bete

s are

at

incr

eas

ed r

isk

of

dev

elo

pin

g d

iab

ete

s, ~

3%

-10

% o

f p

eop

le p

er y

ear

wit

h

pre

dia

bet

es

dev

elo

p d

iab

ete

s.

In m

ost

po

pu

lati

on

s

stu

die

s, t

he

rate

s o

f co

nv

ers

ion

fro

m i

mp

aire

d f

asti

ng

glu

cose

or

imp

air

ed g

luco

se t

ole

ran

ce a

re s

imil

ar,

wit

h

imp

aire

d g

luco

se t

ole

ran

ce

hav

ing

gre

ate

r se

nsi

tiv

ity

bu

t le

ss s

peci

fici

ty.

- P

eop

le w

ith

pre

dia

bete

s h

ave a

tw

o t

o t

hre

efo

ld

incr

eas

ed r

isk

of

card

iov

asc

ula

r d

isea

se c

om

par

ed t

o

adu

lts

wh

o h

ave

no

rmal

glu

cose

to

lera

nce.

- S

ever

al r

and

om

ized

, p

rosp

ect

ive s

tud

ies

of

sub

ject

s

wit

h p

red

iab

ete

s h

ave

do

cum

ente

d b

enef

icia

l ef

fect

s o

f

life

sty

le i

nte

rven

tio

ns

in p

rev

enti

ng

ty

pe

2 d

iab

etes

.

Th

e D

iab

ete

s P

rev

enti

on

Pro

gra

m o

bse

rved

a 5

8%

ris

k

red

ucti

on

in

pro

gre

ssio

n t

o d

iab

etes

ev

en t

ho

ug

h

par

ticip

ants

did

not

mee

t w

eig

ht

loss

an

d m

od

era

te

ph

ysi

cal

act

ivit

y g

oals

.

- M

ult

iple

med

icat

ion

s h

ave

been

sh

ow

n t

o r

edu

ce

inci

den

ce

of

dia

bet

es i

n p

eop

le w

ith

pre

dia

bet

es i

n

ran

do

miz

ed,

do

ub

le-b

lin

ded

tri

als.

In

th

e D

iab

ete

s

Pre

ven

tio

n P

rog

ram

, su

bje

cts

all

oca

ted

to

met

form

in

ther

apy

had

a 3

1%

red

uce

d r

isk

of

con

vers

ion

to

dia

bete

s co

mp

are

d w

ith

th

e c

on

tro

l g

rou

p.

Oth

er

dru

gs,

su

ch a

s acar

bo

se a

nd

ro

sig

lita

zon

e, m

ay r

edu

ce

con

ver

sio

n t

o d

iab

etes

as

wel

l as

card

iov

ascu

lar

even

ts,

bu

t th

e re

sult

s n

eed

to

be c

on

firm

ed b

y o

ther

stu

die

s.

- N

o d

ata

ex

ist

to d

efin

e t

he u

tili

ty o

f m

on

ito

rin

g

Hb

Alc

in

pre

dia

bet

ic p

ati

ents

.

- A

sses

smen

t an

d m

anag

em

ent

of

risk

fact

ors

fo

r

card

iov

asc

ula

r d

isease

, su

ch a

s li

pid

an

d b

loo

d

pre

ssu

res

abn

orm

alit

ies,

sh

ou

ld b

e u

nd

erta

ken

.

Alt

ho

ug

h t

her

e h

ave

been

no

tri

als

in

pre

dia

beti

cs,

the

lip

id a

nd

blo

od

pre

ssu

re t

arg

ets

sho

uld

be

equ

ival

ent

to t

ho

se f

or

typ

e 2

dia

bet

es.

- S

ust

ain

ed a

nd

mo

der

ate

weig

ht

loss

in

peo

ple

wit

h p

red

iab

ete

s is

an

im

po

rtan

t p

red

icto

r o

f a

po

siti

ve

ou

tco

me o

f li

fest

yle

in

terv

enti

on

s.

- It

is

reco

mm

end

ed t

hat

a m

inim

um

of

6 m

on

ths

of

life

sty

le i

nte

rven

tio

n b

e tr

iale

d b

efo

re d

rug

ther

apy

is

con

sid

ered

.

- P

racti

cal

hea

lth

car

e d

eliv

ery

of

life

sty

le a

spec

ts

of

dia

bet

es p

rev

enti

on

req

uir

es f

urt

her

stu

dy

.

- P

harm

aco

ther

apy

may

in

vo

lve

metf

orm

in, w

hic

h

app

ears

to

be

mo

re e

ffic

aci

ou

s in

yo

un

ger

(<

60

yea

rs)

and

mo

re o

verw

eig

ht

peo

ple

. O

ther

dru

gs

may

be o

rlis

tat,

aca

rbo

se o

r a t

hia

zoli

din

edio

ne.

- In

th

e a

bse

nce

of

speci

fic

clin

ical

ind

icat

ion

s,

ther

e is

no

need

fo

r ro

uti

nel

y c

on

du

ctin

g t

he

foll

ow

ing

test

s in

pre

dia

bet

ic p

atie

nts

: c

apil

lary

blo

od

glu

cose

measu

rem

ent,

Hb

A1

c, s

eru

m i

nsu

lin

or

pan

cre

ati

c C

-pep

tid

e, t

ests

fo

r is

chem

ic h

eart

dis

ease

, te

sts

for

mic

rov

asc

ula

r co

mp

lica

tio

ns.

- F

oll

ow

-up

tes

tin

g i

n p

red

iab

ete

s re

qu

ires

a f

orm

al

75

g o

ral

glu

cose

to

lera

nce

test

.

[Th

is p

osi

tio

n s

tate

men

t h

as

no

t a

do

pte

d A

meri

can

Dia

bet

es A

sso

cia

tio

n r

ecen

tly

mo

dif

ica

tio

n t

o

imp

air

ed f

ast

ing

glu

cose

def

init

ion

of

5.6

-6.9

mm

ol/

L.

Th

e a

uth

ors

sta

te t

ha

t su

ch a

lo

w

thre

sho

ld g

luco

se l

eve

l m

ay

cau

se t

he i

mp

air

ed

fast

ing

glu

cose

ca

teg

ori

zati

on

to

lo

se s

pec

ific

ity

an

d p

osi

tive

pre

dic

tive

valu

e a

s a

ris

k fa

cto

r fo

r

dia

bet

es.

T

he r

epo

rt u

ses

the

WH

O d

efin

itio

n o

f

!6

.1 m

mo

l/L

an

d <

7.0

mm

ol/

L]


www.icsi.org

72

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-

val

ue,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s

rati

o,

lik

elih

oo

d r

atio

, n

um

ber

nee

ded

to

tre

at)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Sch

mid

t,

et a

l.,

20

05

Stu

dy

of

sen

siti

vit

y

and

speci

fici

ty

of

a r

isk

pre

dic

tio

n

fun

ctio

n

C

+

79

15

par

tici

pan

ts f

rom

the

Ath

ero

scle

rosi

s

Ris

k i

n C

om

mu

nit

ies

stu

dy

, st

ud

y s

ub

jects

wer

e fr

ee o

f d

iab

etes

at b

asel

ine (

19

87-

19

89

) an

d f

oll

ow

ed

un

til

19

96

-19

98

.

-Th

e o

bje

cti

ve

of

this

stu

dy

was

to d

eri

ve

risk

fun

ctio

ns

to p

red

ict

dia

bete

s w

ith

eq

ual

or

bet

ter

dia

gn

ost

ic p

rop

erti

es t

han

im

pai

red

glu

cose

tole

ran

ce.

- L

og

isti

c re

gre

ssio

n w

as

use

d i

n a

ran

do

m h

alf

of

the

sam

ple

, th

en e

valu

ate

the r

isk

fu

nct

ion

s in

th

e

oth

er h

alf

of

the

sam

ple

.

- R

ule

s b

ase

d o

n r

isk

fu

nct

ion

s in

clu

din

g l

abo

rato

ry

mea

sure

men

ts p

erf

orm

ed g

enera

lly

bet

ter;

a r

isk

fun

ctio

n b

ased

on

wai

st c

ircu

mfe

ren

ce,

hei

gh

t,

hy

per

ten

sio

n, b

loo

d p

ress

ure

, fa

mil

y h

isto

ry o

f

dia

bete

s, e

thn

icit

y a

nd

ag

e w

as p

erf

orm

ed s

imil

arly

to o

ne

base

d o

n f

asti

ng

glu

cose

(are

a u

nd

er

the

curv

e 0

.71

an

d 0

.74

, re

spec

tiv

ely

, p

=0

.2).

- R

ule

s b

ase

d o

n t

he

pre

sen

ce

of

ele

men

ts o

f th

e

met

abo

lic

syn

dro

me

pro

du

ced

sli

gh

tly

less

desi

rab

le

dia

gn

ost

ic p

rop

erti

es (

23

% l

abel

ed a

s h

igh

ris

k a

nd

50

% o

f fu

ture

case

s id

enti

fied

) th

an r

ule

s b

ase

d o

n

risk

fu

ncti

on

in

clu

din

g l

ipid

s (2

0%

lab

eled

as

hig

h

risk

an

d 5

2%

of

futu

re c

ase

s id

enti

fied

).

Met

abo

lic

syn

dro

me

rule

s h

ad s

lig

htl

y l

ess

sen

siti

vit

y (

2%

)

and

sp

ecif

icit

y (

4%

) co

mp

are

d t

o r

ule

s u

sin

g a

clin

ical

cal

cula

tor

or

web

pag

e.

Ru

les

base

d o

n t

he m

eta

bo

lic s

yn

dro

me

crit

eria

are

reaso

nab

le a

lter

nat

ives

to r

ule

s d

eri

ved

fro

m

the

risk

fu

ncti

on

s.

Kim

, et

al.,

20

06

Ran

do

miz

ed,

con

tro

lled

tria

l

A

- 5

2 m

en a

nd

47

wo

men

age

53

.5±

11

.4 y

ear

s

wit

h p

red

iab

ete

s o

r

no

n-d

iab

etic

met

abo

lic

syn

dro

me

wer

e

enro

lled

an

d

ran

do

miz

ed t

o e

ith

er

4m

g r

osi

gli

tazo

ne

trea

tmen

t g

rou

p o

r

no

n-t

reat

ed c

on

tro

l

gro

up

an

d f

oll

ow

ed

for

12

wee

ks.

At

base

lin

e an

d 1

2-w

eek

fo

llo

w-u

p,

sub

jects

wer

e

giv

en a

75

g o

ral

glu

cose

to

lera

nce

tes

t.

Infl

amm

ato

ry m

ark

ers

th

ou

gh

t to

be

card

iov

asc

ula

r

risk

mark

ers

, p

uls

e-w

ave-

vel

oci

ty (

a m

easu

re o

f

arte

rial

sti

ffn

ess

) an

d a

nth

rop

om

etri

cs

wer

e al

so

mea

sure

d.

Ro

sig

lita

zon

e t

reat

men

t si

gn

ific

antl

y i

ncre

ased

circ

ula

tin

g l

evel

s o

f ad

ipo

nec

tin

an

d d

ecr

eas

ed

lev

els

of

CR

P r

elat

ive

to t

he

con

tro

l g

rou

p. T

he

trea

tmen

t g

rou

p a

lso

had

sig

nif

ican

tly

decr

eas

ed

pu

lse-

wav

e-v

elo

cit

y c

om

pare

d t

o t

he

con

tro

l g

rou

p.

Th

ese

data

su

gg

est

th

at

rosi

gli

tazo

ne

ther

apy

may

hav

e an

an

ti-a

thero

gen

ic a

ffect

in

su

bje

cts

wit

h

pre

dia

bet

es.

[Th

is s

tud

y w

as

no

t co

nd

uct

ed i

n a

do

ub

le-

bli

nd

ed p

laceb

o c

on

tro

lled

fa

shio

n.

It

is p

oss

ible

tha

t th

e ro

sig

lita

zon

e g

rou

p h

ad

mo

re i

nte

nsi

ve

life

styl

e ch

an

ges

th

at

cou

ld h

ave

exa

gg

era

ted

th

e

ben

efic

ial

effe

ct o

f ro

sig

lita

zon

e. A

lso

, it

is

dif

ficu

lt t

o i

mp

oss

ible

to

tea

se a

pa

rt t

he

effe

ct o

f

ph

arm

aco

ther

ap

y a

nd

lif

est

yle

ch

an

ges

in

th

is

stu

dy.]



www.icsi.org

73

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-

val

ue,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s

rati

o,

lik

elih

oo

d r

atio

, n

um

ber

nee

ded

to

tre

at)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

No

rris

,

et a

l.,

20

05

Met

a-

anal

ysi

s

M

+

Lit

eratu

re s

ear

ches

wer

e co

nd

uct

ed u

p

to 2

00

3.

Ran

do

miz

ed

con

tro

lled

tri

als

in

any

lan

gu

age

that

exam

ined

weig

ht

loss

or

weig

ht

con

tro

l w

ith

at

leas

t

on

e d

ieta

ry,

ph

ysi

cal

acti

vit

y o

r

beh

avio

ral

inte

rven

tio

n w

ith

foll

ow

-up

gre

ate

r

than

12

mo

nth

s

wer

e se

lect

ed.

A

met

a-an

aly

sis

was

con

du

cted

an

d

effe

cts

wer

e

com

bin

ed u

sin

g a

ran

do

m e

ffects

mo

del

.

Th

e o

bje

cti

ve

of

this

meta

-an

aly

sis

was

to

asse

ss t

he e

ffect

iven

ess

of

weig

ht-

loss

an

d

wei

gh

t-co

ntr

ol

inte

rven

tio

n f

or

adu

lts

wit

h

pre

dia

bete

s.

A t

ota

l o

f 5

16

8 p

arti

cip

ants

wer

e in

clu

ded

in

po

ole

d a

nal

yse

s. F

oll

ow

-up

ran

ged

fro

m 1

to

10

yea

rs.

Co

mp

ared

to

usu

al

care

, fo

ur

stu

die

s

wit

h a

fo

llo

w-u

p o

f 1

yea

r re

du

ced

weig

ht

by

2.8

kg

(9

5%

CI

1.0

-4.7

) an

d d

ecr

eas

ed b

od

y

mas

s in

dex

by

1.4

kg

/m2 (

0.5

-2.3

).

Wei

gh

t

loss

at

2 y

ear

s w

as 2

.7 k

g (

1.9

-3.4

) fr

om

tw

o

stu

die

s.

Mo

des

t im

pro

vem

ents

wer

e n

ote

d i

n

the

few

stu

die

s th

at

exam

ined

gly

cem

ic

con

tro

l, b

loo

d p

ress

ure

, li

pid

s.

Th

e i

nci

den

ce

of

dia

bete

s w

as s

ign

ific

antl

y l

ow

er i

n t

he

inte

rven

tio

n g

rou

ps

vs.

co

ntr

ols

in

3 o

r 5

stu

die

s th

at

exam

ined

th

is o

utc

om

e a

t 3

to

6

yea

rs f

oll

ow

-up

.

Alt

ho

ug

h t

he

wei

gh

t lo

ss a

mo

un

ts

dem

on

stra

ted

in

th

is r

evie

w w

ere

small

, it

app

ears

th

at e

ven

mo

des

t w

eig

ht

loss

may

hav

e h

eal

th b

enef

its

wit

h r

egar

d t

o

card

iov

asc

ula

r d

iseas

e ri

sk f

act

ors

an

d

dev

elo

pm

ent

of

dia

bete

s.



www.icsi.org

74

Au

tho

r/Y

ear

D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-

val

ue,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s

rati

o,

lik

elih

oo

d r

atio

, n

um

ber

nee

ded

to

tre

at)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

McF

arl

ane,

et

al.,

20

07

Do

ub

le-

bli

nd

,

ran

do

m-

ized

con

tro

lled

tria

l, t

he

DR

EA

M

tria

l

A

- T

he

stu

dy

scre

ened

24

,59

2

per

son

s an

d

ran

do

miz

ed 5

,26

9

in 1

91

sit

es

fro

m

21

co

un

trie

s w

ith

a m

edia

n f

oll

ow

-

up

of

3 y

ear

s.

Pat

ien

ts e

nro

lled

wer

e o

lder

th

an 3

0

yea

rs w

ith

pre

dia

bet

es

def

ined

as

imp

aire

d g

luco

se

tole

ran

ce (

fast

ing

pla

sma g

luco

se

<7

, 2

-ho

ur

pla

sma

glu

cose

7.8

-11

mm

ol/

L)

and

/or

imp

aire

d f

asti

ng

glu

cose

(fa

stin

g

pla

sma g

luco

se

6.1

-6.9

mm

ol/

L).

Th

e p

rim

ary

aim

s o

f th

is s

tud

y w

ere

to

tes

t 1

) d

oes

ram

ipri

l p

rev

ent

dia

bete

s? a

nd

2)

do

es

rosi

gli

tazo

ne

pre

ven

t d

iab

etes?

Pri

mar

y o

utc

om

es

of

the

stu

dy

were

in

cid

ent

dia

bete

s (c

on

firm

ed b

y f

ast

ing

pla

sma

glu

cose

>7

or

2-h

ou

r p

lasm

a g

luco

se >

11

.1 o

r d

iag

no

sis

mad

e b

y a

ph

ysi

cian

or

deat

h.

Sec

on

dary

ou

tco

mes

in

clu

ded

ass

essm

ent

of

the

rate

of

con

vers

ion

to

pre

dia

bete

s to

no

rmo

gly

cem

ia a

s

wel

l as

ev

alu

ati

on

of

ram

ipri

l an

d r

osi

gli

tazo

ne

effe

cts

on

card

iore

nal

even

ts.

Res

ult

s:

Ram

ipri

l at

a d

osa

ge

of

15

mg

/d f

or

3.5

yea

rs d

id n

ot

pre

ven

t d

iab

etes.

H

ow

ever

, ra

mip

ril

was

ass

oci

ated

wit

h a

no

nsi

gn

ific

ant

decre

ase

(9%

)

in n

ew-o

nse

t d

iab

ete

s co

mp

are

d t

o p

laceb

o a

nd

was

asso

cia

ted

wit

h a

sig

nif

ican

t in

creas

e (1

6%

) in

th

e

rate

of

con

ver

sio

n t

o n

orm

og

lycem

ia f

rom

im

pai

red

glu

cose

to

lera

nce

an

d i

mp

air

ed f

ast

ing

glu

cose

.

Ro

sig

lita

zon

e w

as

asso

cia

ted

wit

h a

sig

nif

ican

t

dec

reas

ed (

60

%)

in n

ew o

nse

t d

iab

ete

s co

mp

are

d

wit

h p

laceb

o.

Th

is e

ffect

was

con

sist

ent

acr

oss

ag

e,

sex

an

d r

aci

al/e

thn

ic g

rou

ps.

Ad

dit

ion

all

y,

there

was

a si

gn

ific

ant

incre

ase

(7

1%

) in

co

nv

ersi

on

rat

e to

no

rmo

gly

cem

ia a

mo

ng

th

ose

wit

h i

mp

aire

d g

luco

se

tole

ran

ce a

nd

im

pair

ed f

ast

ing

glu

cose

.

Th

e D

RE

AM

tri

al

did

no

t cle

arl

y d

emo

nst

rate

a

dia

bete

s p

rev

enti

on

eff

ect

wit

h r

amip

ril

and

on

ly

sho

wed

a t

ren

d.

Ho

wev

er,

th

e fi

nd

ing

s co

nfi

rmed

the

ben

efic

ial

eff

ects

of

ram

ipri

l o

n g

luco

se

met

abo

lism

.

Th

e ro

sig

lita

zon

e f

ind

ing

s co

nfi

rm o

ther

fin

din

gs

that

th

e d

rug

red

uces

in

suli

n r

esi

stan

ce

and

pre

serv

es

pan

crea

tic

B-c

ell

fu

nct

ion

. H

ow

ever,

du

e to

liv

er

tox

icit

y,

the a

gen

t th

at w

as

act

ual

ly

test

ed (

tro

gli

tazo

ne)

was

wit

hd

raw

n f

rom

th

e

mar

ket

an

d e

ven

tual

ly r

epla

ced

wit

h m

uch

saf

er

thia

zoli

daz

ides

that

wer

e n

ot

speci

fical

ly t

este

d i

n

ran

do

miz

ed c

on

tro

lled

tri

als

for

dia

bete

s

pre

ven

tio

n.

Th

e au

tho

rs s

ug

ges

t th

at u

se o

f an

AC

E i

nh

ibit

or,

wh

en o

therw

ise i

nd

icate

d, w

ou

ld b

e a

pru

den

t

cho

ice

for

pre

dia

beti

cs b

ecau

se t

hey

are

at

incr

eas

ed r

isk

of

card

iov

asc

ula

r d

isea

se.

[Th

is i

s a

rela

tive

ly l

arg

e tr

ial

of

ph

arm

aco

ther

ap

y to

pre

ven

t d

iab

etes

am

on

g

pre

dia

beti

cs. H

ow

eve

r, t

his

art

icle

wa

s a

bri

ef

rep

ort

an

d d

id n

ot

inclu

de

an

y d

eta

ils

of

the

recr

uit

men

t a

nd

ra

nd

om

iza

tio

n p

roce

ss, n

or

did

it

incl

ud

e a

ny

ba

seli

ne t

ab

les.

In

ad

dit

ion

, th

ere

wer

e n

o c

on

fid

ence

inte

rva

ls p

rese

nte

d f

or

the

po

int

est

ima

tes

giv

en i

n t

he t

ext.

]



www.icsi.org

75

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

,

lik

eli

ho

od

rat

io,

nu

mb

er n

eed

ed t

o t

reat

)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Far

ag,

et a

l.,

20

07

Nar

rati

ve

rev

iew

R

- A

no

n-

syst

em

ati

c

rev

iew

of

typ

e 2

dia

bete

s

pre

ven

tio

n

rese

arch

,

incl

ud

ing

pre

ven

tio

n

amo

ng

pre

dia

beti

cs.

Th

ere a

re n

o d

eta

ils

of

ho

w a

rtic

les

wer

e se

lect

ed f

or

incl

usi

on

in

th

e re

vie

w.

Ho

wev

er, th

e a

rtic

le c

ov

ers

sev

eral

imp

ort

ant

area

s o

f d

iab

ete

s p

rev

enti

on

:

Pre

dia

bet

ic s

tate

: d

efin

es p

red

iab

etic

s as

imp

air

ed

fast

ing

glu

cose

of

10

0 t

o 1

25

mg

/dL

an

d/o

r im

pai

red

glu

cose

to

lera

nce

wit

h g

luco

se l

evels

of

14

0 t

o 1

99

mg

/dL

2 h

ou

rs a

fter

an

ora

l lo

ad o

f g

luco

se.

Est

imat

es t

hat

40

% o

f p

eop

le w

ith

im

pair

ed g

luco

se

tole

ran

ce

pro

gre

ss t

o d

iab

etes

.

Lif

est

yle

ch

ang

es:

su

mm

ariz

es f

ind

ing

s th

at

weig

ht

loss

, d

iet

and

ex

ercis

e h

ave

been

sh

ow

n s

epar

atel

y

and

in

co

mb

inat

ion

to

be e

ffect

ive i

n d

ecre

asin

g t

he

inci

den

ce

of

typ

e 2

dia

bet

es i

n h

igh

ris

k p

ati

ents

.

Ph

arm

oco

log

ic i

nte

rven

tio

ns:

su

mm

ariz

es

fin

din

gs

for

sev

eral

typ

es o

f d

rug

s.

Insu

lin

sen

siti

zin

g d

rug

s

(met

form

in,

thia

zoli

din

edio

nes

) an

d o

ral

anti

-dia

bet

ic

agen

ts (

glu

cosi

dase

in

hib

ito

rs)

hav

e b

een

sho

wn

to

be

effe

cti

ve

in r

edu

cin

g i

ncid

ence

of

dia

bet

es i

n p

ati

ents

wit

h i

mp

aire

d g

luco

se t

ole

ran

ce o

r ar

e cu

rren

tly

bei

ng

ex

amin

ed i

n o

ng

oin

g t

rial

s (n

ate

gli

nid

ines

).

Oth

er d

rug

s su

ch a

s A

CE

S, st

atin

s an

d f

ibra

tes

hav

e

inco

nsi

sten

t fi

nd

ing

s fo

r d

iab

etes

pre

ven

tio

n.

Th

ere

is n

ot

suff

icie

nt

evid

ence

for

a p

rote

cti

ve

effe

ct

for

dia

bete

s w

ith

weig

ht-

red

ucin

g a

gen

ts, b

ut

ther

e is

evid

ence

of

gre

ate

r su

cce

ss w

ith

weig

ht

loss

.

Su

rger

y:

su

mm

ariz

es s

tud

ies

fro

m S

wed

en a

nd

US

that

ev

alu

ated

su

rgic

al

inte

rven

tio

ns

for

wei

gh

t lo

ss.

Th

e au

tho

rs c

on

clu

de

that

sev

eral

inte

rven

tio

ns

hav

e b

een

sh

ow

n t

o b

e

effe

cti

ve

in p

rev

enti

ng

dia

bet

es,

incl

ud

ing

lif

est

yle

mo

dif

icati

on

s as

wel

l

as a

nti

-dia

bet

ic p

har

mac

oth

erap

y.



www.icsi.org

76

Au

tho

r/Y

ear

D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-

val

ue,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s

rati

o,

lik

elih

oo

d r

atio

, n

um

ber

nee

ded

to

tre

at)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Tu

om

ileh

to,

et

al.,

20

01

Fin

nis

h

Dia

bet

es

Pre

ven

tio

n

Stu

dy

RC

T

A

+

52

2 m

idd

le-a

ged

,

ov

erw

eig

ht

sub

juct

s

(17

2 m

en a

nd

35

0

wo

men

, m

ean

ag

e 5

5

yea

rs,

mea

n B

MI

31

kg

/m2)

wit

h i

mp

air

ed

glu

cose

wer

e

ran

do

miz

ed t

o e

ith

er

ind

ivid

ual

ized

cou

nse

lin

g a

imed

at

red

ucin

g w

eig

ht

and

tota

l fa

t in

tak

e an

d

incr

eas

ing

ph

ysi

cal

acti

vit

y a

nd

fib

er

inta

kes

(in

terv

enti

on

gro

up

) o

r a

con

tro

l

gro

up

. T

he

mean

du

rati

on

of

foll

ow

-up

was

3.2

year

s.

Th

e p

rim

ary

aim

of

this

stu

dy

was

to

det

erm

ine t

he

feas

ibil

ity

of

a li

fest

yle

in

terv

enti

on

to

del

ay o

r

pre

ven

t in

cid

ence

ty

pe 2

dia

bet

es.

Th

e m

ean

(S

D)

amo

un

t o

f w

eig

ht

lost

betw

een

bas

elin

e an

d t

he

end

of

year

1 w

as 4

.2 (

5.1

) k

g i

n

the

inte

rven

tio

n g

rou

p a

nd

0.8

(3

.7)

kg

in

th

e co

ntr

ol

gro

up

(p

<0

.00

1).

A

fter

tw

o y

ears

, th

e n

et w

eig

ht

loss

was

3.5

(5

.5)

kg

in

th

e in

terv

enti

on

gro

up

an

d

0.8

(5

.5)

kg

in

th

e co

ntr

ol

gro

up

(p

<0

.00

1).

Th

e cu

mu

lati

ve i

ncid

ence

of

dia

bete

s aft

er f

ou

r

yea

rs w

as

11

% (

95

% C

I 6

to

15

%)

in t

he

inte

rven

tio

n g

rou

p a

nd

23

% (

95

% C

I 1

7 t

o 2

9%

) in

the

con

tro

l g

rou

p.

In

th

e tr

ial,

th

e ri

sk o

f d

iab

etes

was

red

uced

by

58

% (

p<

0.0

01

) in

th

e in

terv

enti

on

gro

up

.

Th

e au

tho

rs c

on

clu

de

that

th

e re

du

cti

on

in

inci

den

ce

of

dia

bet

es w

as a

dir

ectl

y a

sso

ciat

ed

wit

h c

han

ges

in l

ifes

tyle

.

[In

tere

stin

gly

, a

chie

vin

g a

rela

tive

ly m

od

est

ph

ysic

al

act

ivit

y g

oa

l o

f 4

hr/

week

wa

s a

sso

cia

ted

wit

h a

sig

nif

ica

nt

red

ucti

on

in

in

cid

ent

dia

bet

es

in s

ub

jects

wh

o d

id n

ot

lose

wei

gh

t.

It i

s p

oss

ible

tha

t a

ny

typ

e o

f p

hys

ica

l a

cti

vity

is

ben

efic

ial.

]

Lin

dst

röm

, et

al.,

20

06

Fin

nis

h

Dia

bet

es

Pre

ven

tio

n

Stu

dy

(fo

llo

w-

up

stu

dy

)

RC

T

A

Ø

25

6 i

nte

rven

tio

n a

nd

25

7 c

on

tro

l ar

tici

pan

ts

wh

o w

ere

stil

l fr

ee

of

dia

bete

s af

ter

the

acti

ve

inte

rven

tio

n

per

iod

of

4 y

ear

s

(Tu

om

ileh

to,

et a

l.,

20

01

) w

ere

furt

her

foll

ow

ed u

p f

or

a

med

ian

of

3 y

ear

s, f

or

a to

tal

med

ian

fo

llo

w-

up

of

7 y

ear

s.

Th

e p

rim

ary

ou

tco

mes

of

this

stu

dy

was

inci

den

t

typ

e 2

dia

bete

s.

Du

rin

g t

he t

ota

l fo

llo

w-u

p,

the i

ncid

ence

of

dia

bete

s

was

4.3

an

d 7

.4 p

er

10

0 p

erso

n y

ear

s in

th

e

inte

rven

tio

n a

nd

co

ntr

ol

gro

up

s, r

esp

ecti

vely

(p=

0.0

00

1),

in

dic

ati

ng a

43

% r

edu

cti

on

in

rel

ativ

e

risk

. T

he

risk

red

uct

ion

was

rela

ted

to

su

cce

ss i

n

ach

iev

ing

th

e in

terv

enti

on

go

als

of

wei

gh

t lo

ss,

red

uced

in

tak

e o

f to

tal

satu

rate

d f

at

and

in

crea

sed

ph

ysi

cal

act

ivit

y a

nd

fib

er i

nta

ke.

Ben

efic

ial

life

sty

le c

han

ges

in t

he

inte

rven

tio

n g

rou

ps

wer

e

sust

ain

ed a

fter

the

dis

con

tin

uat

ion

of

the

inte

rven

tio

n,

and

th

e c

orr

esp

on

din

g i

ncid

ence

rate

s

du

rin

g t

he

po

st f

oll

ow

-up

per

iod

were

4.6

an

d 7

.2

(p=

0.4

01

), i

nd

icat

ing

a 3

6%

red

uct

ion

in

rel

ati

ve

risk

.

Th

e au

tho

rs c

on

clu

de

that

th

e re

sult

s fr

om

th

e

exte

nd

ed f

oll

ow

-up

of

the F

inn

ish

Dia

bete

s

Pre

ven

tio

n S

tud

y s

ho

w t

hat

th

e ef

fect

of

life

sty

le

inte

rven

tio

n o

n d

iab

etes

ris

k d

oes

no

t d

isap

pear

afte

r ac

tiv

ity

lif

esty

le c

ou

nse

lin

g i

s st

op

ped

.

Th

e au

tho

rs a

ckn

ow

led

ge s

om

e li

mit

atio

ns

to t

his

stu

dy

. F

irst

, th

e an

aly

ses

rela

ted

to

th

e p

ost

-

inte

rven

tio

n p

erio

d w

ere

no

t p

art

of

the o

rig

inal

pro

toco

l, a

nd

po

st-h

oc r

esu

lts

sho

uld

be

inte

rpre

ted

wit

h c

auti

on

as

the

foll

ow

-up

was

no

t

con

sid

ered

in

th

e o

rig

inal

sam

ple

siz

e c

alcu

lati

on

.

Sec

on

d,

the

low

dro

p-o

ut

rate

su

gg

ests

a h

igh

ly

hea

lth

co

nsc

iou

s p

op

ula

tio

n, p

rob

ably

mo

re s

o

than

th

e g

ener

al p

op

ula

tio

n.



www.icsi.org

77

Au

tho

r/Y

ear

D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-

val

ue,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s

rati

o,

lik

elih

oo

d r

atio

, n

um

ber

nee

ded

to

tre

at)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Li,

et

al.,

20

08

Ch

ina

Da

Qin

g

Dia

bete

s

Pre

ven

tio

n

Stu

dy

RC

T

A

- 5

77

ad

ult

s w

ith

imp

air

ed g

luco

se

tole

ran

ce

fro

m 3

3

clin

ics

in C

hin

a

wer

e ra

nd

om

ly

assi

gn

ed t

o e

ith

er a

con

tro

l g

rou

p o

r o

ne

of

3 l

ifes

tyle

inte

rven

tio

n g

rou

ps

(die

t, e

xer

cis

e o

r

die

t p

lus

exer

cise

).

Th

e g

oal

of

the d

iet

inte

rven

tio

n w

as

to

incr

eas

e f

ruit

an

d

veg

etab

le i

nta

ke

and

low

er a

lco

ho

l an

d

sug

ar i

nta

ke.

Th

e

go

al o

f th

e e

xer

cise

inte

rven

tio

n w

as

to

was

to

in

creas

e

leis

ure

tim

e p

hy

sica

l

acti

vit

y.

Th

e in

terv

enti

on

was

co

nd

uct

ed f

or

6

yea

rs w

ith

lon

git

ud

inal

fo

llo

w-

up

fo

r 2

0 y

ears

.

Th

e p

rim

ary

ou

tco

mes

of

this

stu

dy

wer

e

inci

den

t d

iab

etes

, C

VD

in

cid

ence

and

mo

rtali

ty,

and

all

-cau

se m

ort

alit

y i

n t

he

inte

rven

tio

n g

rou

ps

com

bin

ed a

nd

th

e co

ntr

ol

gro

up

.

Co

mp

ared

to

par

tici

pan

ts i

n t

he c

on

tro

l g

rou

p,

tho

se i

n t

he

inte

rven

tio

n g

rou

ps

com

bin

ed h

ad

a 5

1%

lo

wer

in

cid

ence

of

dia

bete

s (H

aza

rd

rati

o 0

.49

[9

5%

CI

0.3

3-0

.73

]) d

uri

ng

th

e 6

-

yea

r in

terv

enti

on

per

iod

an

d 4

2%

lo

wer

(0

.57

,

[0.4

1-0

.81

]) o

ver

th

e 2

0-y

ear

fo

llo

w-u

p p

erio

d

afte

r co

ntr

oll

ing

fo

r ag

e an

d c

lin

ic c

ente

r.

Th

ere w

as n

o s

ign

ific

ant

dif

fere

nce

bet

wee

n

inte

rven

tio

n a

nd

co

ntr

ol

gro

up

s w

ith

reg

ard

to

CV

D e

ven

ts o

r m

ort

alit

y,

or

all-

cau

se m

ort

alit

y

(bu

t w

ere n

ot

po

wer

ed t

o d

etec

t su

ch

dif

fere

nces

).

Res

ult

s fo

r ea

ch i

nte

rven

tio

n a

rm (

die

t alo

ne,

exer

cis

e a

lon

e, d

iet

plu

s ex

erci

se)

wer

e n

ot

pre

sen

ted

.

Th

e au

tho

rs c

on

clu

de

that

th

e re

du

ctio

n i

n

dia

bete

s in

cid

ence

ob

serv

ed d

uri

ng

th

e 6-

yea

r in

terv

enti

on

per

sist

ed f

or

two

dec

ades

.

Th

e au

tho

rs c

ite g

rou

p-b

ased

lif

esty

le

inte

rven

tio

ns

of

6 y

ears

as

pre

ven

tiv

e o

f

dia

bete

s.

Lim

itati

on

s o

f th

is s

tud

y i

ncl

ud

e th

e p

assi

ve

ascer

tain

men

t o

f o

utc

om

es

du

rin

g t

he

po

st-

inte

rven

tio

n p

erio

d. T

his

may

ex

pla

in t

he

ob

serv

ed l

ow

er r

ate

of

incid

ent

dia

bet

es.

Ho

wev

er,

this

bia

s w

as n

ot

syst

emat

ic a

nd

lik

ely

aff

ect

ed b

oth

co

ntr

ol

and

tre

atm

ent

gro

up

s si

mil

arly

.

[Th

ere i

s n

o d

eta

iled

des

crip

tio

n o

f th

e

inte

rven

tio

n –

ho

w i

t w

as

deli

vere

d,

wh

at

wa

s in

clu

ded

. B

eca

use

th

e a

uth

ors

nei

ther

pre

sen

t n

or

dis

cuss

fin

din

gs

for

the

dif

fere

nt

trea

tmen

t a

rms,

it

is i

mp

oss

ible

to

asc

ert

ain

wh

ich

co

mp

on

ents

of

the

life

style

inte

rven

tio

ns

wer

e m

ost

im

po

rta

nt.

Ad

dit

ion

all

y, a

s re

ad

ers,

we

are

un

ab

le t

o

det

erm

ine

wh

at

effe

ct

the

gro

up

dyn

am

ic

mig

ht

ha

ve

ha

d o

n t

he l

ifes

tyle

inte

rven

tio

ns.

]



www.icsi.org

78

Au

tho

r/Y

ear

D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-

val

ue,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s

rati

o,

lik

elih

oo

d r

atio

, n

um

ber

nee

ded

to

tre

at)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Th

e D

iab

etes

Pre

ven

tio

n

Pro

gra

m

Res

earc

h

Gro

up

(DP

P),

20

05

RC

T

A

Ø

Par

ticip

ants

wer

e

ran

do

mly

ass

ign

ed

to m

etfo

rmin

(n=

58

7),

tro

gli

tazo

ne

(n=

58

5),

do

ub

le

pla

ceb

o (

n=

58

2),

or

inte

nsi

ve l

ifest

yle

inte

rven

tio

n

(n=

58

9).

Th

e p

rim

ary

en

d p

oin

t o

f th

is s

tud

y w

as d

ela

y

or

pre

ven

tio

n o

f ty

pe

2 d

iab

ete

s w

ith

trig

lita

zon

e co

mp

ared

to

oth

er t

reatm

ents

.

Beca

use

of

con

cern

s o

f li

ver

to

xic

ity

, th

e

tro

gli

tazo

ne

arm

was

dis

con

tin

ued

bef

ore

th

e

stu

dy

’s e

nd

. D

uri

ng

th

e m

ean

0.9

year

s o

f

tro

gli

tazo

ne

treat

men

t, t

he d

iab

ete

s in

cid

ence

rate

was

3 c

ases

/10

0,0

00

per

son-y

ears

,

com

par

ed w

ith

12

, 6

.7,

and

5.1

cas

es/1

00

,00

0

per

son

-yea

rs i

n t

he

pla

ceb

o,

met

form

in a

nd

life

sty

le i

nte

rven

tio

n g

rou

ps

(p<

0.0

00

1

tro

gli

tazo

ne

vs.

pla

ceb

o,

p=

0.0

2 t

rig

lita

zon

e

vs.

met

form

in,

p=

0.1

8 t

rog

lita

zon

e v

s.

life

sty

le).

Th

e au

tho

rs b

elie

ve

the

trig

lita

zon

e ef

fect

was

in

par

t d

ue t

o i

mp

rov

ed i

nsu

lin

sen

siti

vit

y w

ith

main

ten

ance

of

insu

lin

secr

etio

n.

Du

rin

g 3

yea

rs a

fter

tri

gli

tazo

ne

wit

hd

raw

al,

the d

iab

etes

in

cid

ence

was

nea

rly

id

enti

cal

to p

lace

bo

gro

up

.

Th

eref

ore

, th

e au

tho

rs c

on

lud

e t

hat

trig

lita

zon

e m

ark

edly

red

uced

th

e in

cid

ence

of

dia

bete

s d

uri

ng

tre

atm

ent,

bu

t th

is a

ctio

n

did

no

t p

ersi

st b

eyo

nd

th

e l

imit

ed p

erio

d o

f

use

.

Th

ere w

as i

nsu

ffic

ien

t d

ata

(o

nly

10

cas

es o

f

dia

bete

s d

uri

ng

33

0 p

erso

n-y

ear

s o

f fo

llo

w-

up

fo

r tr

og

lita

zon

e ar

m)

to e

xam

ine a

ny

effe

cts

acco

rdin

g t

o a

ge,

eth

nic

ity

, B

MI.

Ho

wev

er,

it a

pp

ears

th

at t

rog

lita

zon

e

trea

tmen

t w

as

the

mo

st e

ffecti

ve o

f all

trea

tmen

t ar

ms.

Dia

bete

s

Pre

ven

tio

n

Pro

gra

m

Res

earc

h

Gro

up

, 2

00

2

DP

P

RC

T

A

+

3,2

34

no

nd

iab

etic

per

son

s w

ith

elev

ated

fas

tin

g a

nd

po

st-l

oad

pla

sma

glu

cose

wer

e

ran

do

miz

ed t

o

pla

ceb

o,

metf

orm

in

or

life

sty

le t

her

apy

.

Th

e p

rim

ary

ou

tco

me

of

incid

ent

dia

bete

s.

Th

e av

erag

e fo

llo

w-u

p t

ime

was

2.8

year

s.

Th

e in

cid

ence

of

dia

bet

es w

as 1

1, 7

.8 a

nd

4.8

case

s p

er 1

00

per

son-y

ear

s in

th

e p

lace

bo

,

met

form

in a

nd

lif

est

yle

gro

up

s, r

esp

ecti

vel

y.

Co

mp

ared

to

pla

ceb

o,

the

life

sty

le i

nte

rven

tio

n

red

uce

d t

he i

ncid

ence

of

dia

bete

s b

y 5

8%

(95

% C

I 4

8 t

o 6

6%

), a

nd

th

e m

etf

orm

in

inte

rven

tio

n r

edu

ced

th

e in

cid

ence

of

dia

bet

es

by

31

% (

95

% C

I 1

7 t

o 4

3%

).

In t

his

ran

do

miz

ed t

rial,

bo

th m

etf

orm

in a

nd

life

sty

le c

han

ges

red

uce

d t

he i

nci

den

ce o

f

dia

bete

s co

mp

ared

to

pla

ceb

o i

n p

erso

ns

at

hig

h r

isk

. H

ow

ever

, th

e l

ifes

tyle

in

terv

enti

on

was

sig

nif

ican

tly

mo

re e

ffec

tiv

e th

an

met

form

in.

[In

tere

stin

gly

, th

e l

ifes

tyle

gro

up

lo

st m

ore

weig

ht

com

pa

red

to

th

e m

etf

orm

in a

nd

pla

ceb

o g

rou

ps.

H

ow

eve

r, t

he s

tud

y w

as

no

t

des

ign

ed t

o t

est

th

e r

ela

tive

co

ntr

ibu

tio

ns

of

die

tary

ch

an

ges

, in

crea

sed

ph

ysi

cal

act

ivit

y

an

d w

eig

ht

loss

.]



www.icsi.org

79

Conclusion Grading Worksheet B – Annotation #11 (A1c)


Work

Gro

up

’s C

on

clu

sion

:

A1c

targ

et i

n t

ype

2 d

iabet

es i

s ai

med

at

reduci

ng m

icro

vas

cula

r co

mpli

cati

ons

whil

e not

incr

easi

ng r

isk o

f m

orb

idit

y o

r m

ort

alit

y.

• A

ll p

atie

nts

wit

h t

ype

2 d

iabet

es s

hould

aim

to a

chie

ve

an A

1c

less

than

8%

. T

his

wil

l re

duce

mic

rovas

ucl

ar d

isea

se a

nd n

ot

incr

ease

ris

k s

ubst

anti

ally

.

• M

ost

(m

any)

pat

ients

wit

h t

ype

2 d

iabet

es m

ay d

eriv

e ad

dit

ional

ben

efit

in r

educt

ion o

f m

icro

vas

ucl

ar d

isea

se b

y r

each

ing a

tar

get

A1c

less

than

7%

and n

ot

incr

ease

ris

ks

as l

ong a

s th

e ta

rget

is

not

A1c

less

than

6%

.

Con

clu

sio

n G

rad

e:

II

Au

tho

r/

Year

Desi

gn

Ty

pe

Cla

ss

Qu

al-

ity

(+,–

,ø)

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

easu

re(s

)/R

esu

lts

(e.g

., p

-valu

e, c

on

fiden

ce

inte

rval,

rela

tiv

e r

isk

, od

ds

rati

o,

likeli

ho

od

rati

o,

nu

mb

er n

eed

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

en

ts

(ita

lici

zed)

Gaed

e

et

al.

,

20

08

Ran

-

do

m-

ized

co

nt-

roll

ed

tria

l

(RC

T)

A

+

-- F

oll

ow

-up

stu

dy

aft

er

co

mp

leti

on

of

inte

rven

tio

nal

stu

dy

(S

ten

o-2

Stu

dy

).

-- 1

60

pati

en

ts (

mean

ag

e 5

5.1

years

at

base

lin

e)

wit

h t

yp

e 2

dia

bete

s an

d

mic

roalb

inu

ria r

an

do

mly

ass

ign

ed t

o

inte

nsi

ve t

hera

py

gro

up

([I

G],

targ

et

Hb

A1

c <

6.5

%, fa

stin

g c

ho

lest

ero

l <

17

5 m

g/d

l, f

ast

ing

tri

gly

ceri

des

< 1

50

mg

/dl,

blo

od

pre

ssu

re <

13

0/8

0 m

m

Hg

, an

d f

ocu

sed

beh

avio

r

mo

dif

icati

on

) an

d a

con

ven

tion

al

(CG

) m

ult

ifacto

rial

treatm

en

t g

rou

p.

-- A

ll p

ati

en

ts r

eceiv

ed

ren

in-

an

gio

ten

sin

sy

stem

blo

ck

ers

and

lo

w-

do

se a

spir

in.

-- 3

pati

en

ts w

ith

dre

w, 2

7 d

ied

du

rin

g

inte

rven

tio

nal

stu

dy

, le

av

ing

13

0 p

ts

for

start

of

foll

ow

-up

stu

dy

.

-- 3

7 d

ied

du

rin

g f

oll

ow

-up

peri

od

,

leav

ing

93

sub

jects

co

mp

leti

ng

foll

ow

-up

stu

dy

.

-- P

rim

ary

en

d p

oin

t in

fo

llo

w-u

p

tria

l w

as

tim

e t

o d

eath

(an

y c

au

se),

wit

h s

eco

nd

ary

en

d p

oin

ts b

ein

g

death

fro

m c

ard

iovasc

ula

r (C

V)

cau

ses,

an

d c

om

po

site

of

CV

dis

ease

ev

en

ts.

-- T

ota

l m

ean

fo

llo

w-u

p t

ime 1

3.3

years

(7

.8 y

ears

in

in

terv

en

tio

nal

stu

dy

an

d 5

.5 y

ears

fo

r o

bse

rvati

on

al

foll

ow

-up

).

-- U

sed

in

ten

tio

n-t

o-t

reat

pri

ncip

le

-- B

oth

gro

up

s si

mil

ar

at

base

lin

e

-- M

easu

red

resu

lts

were

as

foll

ow

s:

BP

(m

ean

sy

sto

lic/d

iast

oli

c m

m H

g):

I

G:

en

d o

f in

terv

en

tio

n:

13

1/7

3;

end

of

foll

ow

-up

: 1

40

/74

C

G:

en

d o

f in

terv

en

tio

n:

14

6/7

8;

en

d o

f fo

llo

w-u

p:

146

/73

H

bA

1c (

mean

%):

IG

: en

d o

f in

terv

en

tio

n:

7.9

;

en

d o

f fo

llo

w-u

p:

7.7

C

G:

en

d o

f in

terv

en

tio

n:

9.0

; en

d o

f fo

llo

w-u

p:

8.0

Fast

ing

to

tal

ch

ole

stero

l (m

ean

mg

/dl)

:

I

G:

en

d o

f in

terv

en

tio

n:

15

9;

en

d o

f fo

llo

w-u

p:

14

7

C

G:

en

d o

f in

terv

en

tio

n:

21

6;

en

d o

f fo

llo

w-u

p:

15

5

Fast

ing

tri

gly

ceri

des

(med

ian

mg

/dl)

:

I

G:

en

d o

f in

terv

enti

on

: 1

15

; en

d o

f fo

llo

w-u

p:

99

C

G:

en

d o

f in

terv

en

tio

n:

15

9;

en

d o

f fo

llo

w-u

p:

14

8

-- D

uri

ng

en

tire

13

.3 y

ears

of

foll

ow

-up

, 2

4 I

G p

ts d

ied

an

d 4

0 C

G p

ts d

ied

(hazard

rati

o [

HR

] 0

.54

; p

=0

.02

)

-- 9

IG

pts

die

d o

f C

V c

au

ses

an

d 1

9 C

G p

ts d

ied

of

CV

cau

ses

(HR

0.4

3;

p=

0.0

4)

-- T

ota

l C

V e

ven

ts:

51

in

IG

, 1

58

in

CG

(H

R 0

.41

; p

<0

.00

1);

n

o e

vid

en

ce o

f

ch

an

ge i

n H

R o

ccu

rred

betw

een

en

d o

f in

terv

en

tion

an

d f

inal

ob

serv

ati

on

al

foll

ow

-up

-- D

iab

eti

c n

ep

hro

path

y d

ev

elo

ped

in

20

IG

pts

an

d 3

7 C

G p

ts (

rela

tiv

e r

isk

[RR

] 0

.44

; p

=0

.00

4)

-- P

rog

ress

ion

of

dia

beti

c r

eti

no

path

y o

ccu

rred

in

41

IG

pts

an

d 5

4 C

G p

ts (

RR

0.5

7;

p=

0.0

1)

-- A

uto

no

mic

neu

rop

ath

y p

rog

ress

ed

in

39

IG

pts

an

d i

n 5

2 C

G p

ts (

RR

0.5

3;

p=

0.0

04

); p

eri

ph

era

l n

eu

rop

ath

y p

rog

ress

ion

was

no

t si

gn

ific

an

tly

dif

fere

nt

betw

een

th

e t

wo

gro

up

s

-- D

iffe

ren

ces

in h

yp

og

lycem

ic e

pis

od

es

were

no

t si

gn

ific

an

t b

etw

een

th

e t

wo

gro

up

s (p

=0

.15

tre

nd

fo

r m

ore

ep

iso

des

in I

G)

- -

Du

rin

g e

nti

re f

oll

ow

-up

peri

od

, d

eath

rate

in

CG

was

50

%;

au

tho

rs s

tate

th

is

un

ders

core

s p

oo

r p

rog

no

sis

wit

ho

ut

inte

nsi

ve t

reatm

en

t.

-- S

tud

y w

as

no

t d

esi

gn

ed

to

sho

w w

hic

h e

lem

en

ts o

f in

ten

siv

e

treatm

en

t co

ntr

ibu

ted

mo

st t

o t

he

CV

ris

k r

ed

ucti

on

.

-- S

ign

ific

an

t d

iffe

ren

ces

in r

isk

facto

rs b

etw

een

th

e t

wo

gro

ups

betw

een

th

e i

nte

rven

tion

ph

ase

an

d f

inal

foll

ow

-up

ten

ded

to

co

nv

erg

e (

all

pts

were

off

ere

d

inte

nsi

ve t

reatm

en

t aft

er

inte

rven

tio

n s

tud

y e

nd

ed

), b

ut

tim

e t

o f

irst

CV

ev

en

ts c

on

tin

ued

to d

iverg

e;

au

tho

rs s

tate

d t

hat

this

pro

vid

ed e

vid

ence t

hat

earl

y

inte

rven

tio

n (

inte

nsi

ve t

reatm

en

t)

co

nti

nu

es t

o s

ho

w b

en

efi

t lo

ng-

term

.

[No

te t

ha

t a

lth

ou

gh

ori

gin

al

Hb

A1

c g

oa

l fo

r in

ten

sive

trea

tmen

t w

as

< 6

.5%

yet

avg

., a

t

en

d o

f fo

llo

w-u

p w

as

7.7

%,

un

ders

cori

ng

th

e d

iffi

cu

lty i

n

att

ain

ing

ag

gre

ssiv

e H

bA

1c

go

als

.]

Upd

ated

Thi

rteen

th E

ditio

n, M

ay 2

009.


www.icsi.org

80

Conclusion Grading Worksheet B – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotation #11 (A1c) Thirteenth Edition/May 2009

Au

tho

r/Y

ear

D

esig

n

Ty

pe

Cla

ss

Qu

alit

y

(+,–

,ø)

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s

(e.g

., p

-val

ue,

co

nfi

den

ce i

nte

rval,

rela

tiv

e ri

sk,

od

ds

rati

o, li

keli

ho

od

rati

o, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Sel

vin

et

al.

,

20

04

Met

a-

anal

ysi

s

M

ø

-- M

eta

-an

aly

sis

of

pro

spec

tiv

e

ob

serv

atio

nal

(co

ho

rt)

stu

die

s

on

th

e as

socia

tio

n b

etw

een

Hb

A1

c le

vels

an

d i

nci

den

t

card

iov

asc

ula

r d

isease

,

incl

ud

ing

fata

l an

d n

on

fata

l

my

oca

rdia

l in

farc

tio

n,

ang

ina

and

isc

hem

ic h

eart

dis

ease

,

cere

bro

vas

cula

r d

iseas

e (f

atal

and

no

nfa

tal

stro

ke),

per

iph

era

l

arte

rial

dis

eas

e, a

nd

a c

om

bin

ed

ou

tco

me

that

incl

ud

es

coro

nary

dis

ease

an

d s

tro

ke

-- T

yp

e 2

dia

bet

es

analy

zed

sep

arat

ely

fro

m t

yp

e 1

-- R

and

om

eff

ect

s m

od

el

use

d

to p

oo

l th

e r

esu

lts

-- T

ota

l o

f 1

7 s

tud

y r

epo

rts

incl

ud

ed,

rep

rese

nti

ng

13

un

iqu

e sa

mp

les

(10

gro

up

s o

f

typ

e 2

dia

beti

cs –

in

clu

ded

UK

PD

S s

tud

ies;

to

tal

n=

74

35

for

10

stu

die

s)

-- A

dju

stm

ent

for

po

ssib

le

con

fou

nd

ing

fact

ors

var

ied

con

sid

erab

ly –

ab

ou

t 5

0%

of

stu

die

s u

sed

au

tom

atic

ste

pw

ise

met

ho

ds

for

det

erm

inin

g

mu

ltiv

aria

te m

od

els;

on

ly 3

stu

die

s si

mu

ltan

eou

sly

ad

just

ed

for

kn

ow

n c

ard

iov

ascu

lar

risk

fact

ors

su

ch a

s ag

e, g

end

er,

lip

id l

evel

s, b

loo

d p

ress

ure

an

d

smo

kin

g

-- P

oo

led

rel

ativ

e r

isk

fo

r to

tal

card

iov

asc

ula

r d

isease

(1

0 i

nd

epen

den

t

dat

ase

ts o

f co

ron

ary

dis

ease

alo

ne, st

rok

e

alo

ne,

and

co

mb

ined

str

ok

e a

nd

co

ron

ary

dis

ease

in

ty

pe

2 d

iab

eti

cs)

was

1.1

8 (

95

%

CI,

1.1

0 t

o 1

.26

) fo

r eac

h 1

% i

ncr

ease

in

Hb

A1

c.

-- F

or

the

5 i

nd

epen

den

t st

ud

ies

of

fata

l

and

no

nfa

tal

coro

nar

y d

isea

se r

isk

, th

e

po

ole

d r

elat

ive

risk

was

1.1

5 (

95

% C

I,

1.0

6 t

o 1

.20

), w

ith

th

e r

elat

ive

risk

fo

r fa

tal

coro

nar

y d

iseas

e b

ein

g 1

.16

(9

5%

CI,

1.0

7

to 1

.26

) fo

r ea

ch 1

% i

ncre

ase

in

Hb

A1

c.

-- F

or

the

3 i

nd

epen

den

t st

ud

ies

that

incl

ud

ed s

tro

ke

risk

ass

essm

ent,

th

e p

oo

led

rela

tiv

e r

isk

was

1.1

7 (

95

% C

I, 1

.09

to

1.2

5)

for

each

1%

in

creas

e in

Hb

A1

c.

-- F

or

the

3 i

nd

epen

den

t st

ud

ies

that

incl

ud

ed p

erip

her

al a

rter

ial

dis

ease

ris

k

asse

ssm

ent,

th

e p

oo

led

rela

tiv

e r

isk

was

1.2

8 (

95

% C

I, 1

.18

to

1.3

9).

-- S

mal

l n

um

ber

of

stu

die

s li

mit

ed t

he

abil

ity

to

asc

ert

ain

im

po

rtan

t so

urc

es

of

het

ero

gen

eit

y a

mo

ng

th

e st

ud

ies.

-- D

ata

anal

ysi

s su

pp

ort

s m

od

era

te i

ncr

eas

e in

card

iov

asc

ula

r ri

sk w

ith

in

cre

asi

ng

Hb

A1

c

lev

els

in

ty

pe

1 a

nd

ty

pe 2

dia

beti

cs.

-- I

n s

om

e st

ud

ies,

ass

oci

atio

n o

f

card

iov

asc

ula

r d

isease

wit

h i

ncre

asi

ng

Hb

A1

c

lev

els

was

in

dep

end

ent

of

oth

er

kn

ow

n

card

iov

asc

ula

r ri

sk f

acto

rs.

-- L

inear

rel

atio

nsh

ip o

f car

dio

vas

cula

r ri

sk t

o

Hb

A1

c le

vels

ass

um

ed i

n s

tud

ies,

bu

t n

ot

clea

r

if t

his

is

act

uall

y t

he

cas

e.

-- F

utu

re R

CT

s n

eed

ed t

hat

sp

ecif

ical

ly a

nsw

er

the

qu

est

ion

of

the

rela

tio

nsh

ip o

f g

lycem

ic

con

tro

l (s

peci

fica

lly

Hb

A1

c le

vels

) to

card

iov

asc

ula

r d

isease

an

d d

isea

se r

isk

.


www.icsi.org

81

Au

tho

r/Y

ear

D

esig

n

Ty

pe

Cla

ss

Qu

alit

y

(+,–

,ø)

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s

(e.g

., p

-val

ue,

co

nfi

den

ce i

nte

rval,

rela

tiv

e ri

sk,

od

ds

rati

o, li

keli

ho

od

rati

o, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Ab

rair

a, e

t al.

,

19

97

RC

T

A

_

-- F

easi

bil

ity

stu

dy

co

mp

arin

g

stan

dar

d v

s. i

nte

nsi

ve

insu

lin

ther

apy

-- 1

53

men

wit

h n

on-i

nsu

lin

dep

end

ent

dia

bet

es (

NID

DM

)

wer

e en

roll

ed,

aver

age a

ge

60

yea

rs,

hav

ing

dia

bete

s fo

r an

avera

ge

of

7.8

year

s, w

ith

po

or

gly

cem

ic c

on

tro

l (m

ean

bas

elin

e

Hb

A1

c >

9%

)

-- A

bo

ve p

ts r

and

om

ized

to

a

stan

dar

d i

nsu

lin

tre

atm

ent

gro

up

(SG

, n

=7

8, 1

mo

rnin

g i

nsu

lin

inje

ctio

n p

er d

ay)

and

an

inte

nsi

ve t

reat

men

t g

rou

p (

IG,

n=

75

, st

epp

ed p

lan

)

-- A

ssess

ed c

ard

iov

asc

ula

r

even

ts (

new

my

oca

rdia

l

infa

rcti

on

s, c

on

ges

tiv

e h

ear

t

fail

ure

, st

rok

e,

amp

uta

tio

ns,

card

iov

asc

ula

r m

ort

ali

ty,

ang

ina/

coro

nary

dis

ease

,

ang

iop

last

y/C

AB

G, T

IAs,

per

iph

era

l v

ascu

lar

dis

eas

e

-- 3

8%

of

pts

had

kn

ow

n p

re-

exis

tin

g C

V d

iseas

e

-- S

amp

le s

ize a

nd

du

rati

on o

f

feas

ibil

ity

tri

al

no

t p

ow

ered

to

dem

on

stra

te a

tre

atm

ent

eff

ect

on

CV

dis

ease

, b

ut

ob

ject

ive

was

to

ass

ess

freq

uen

cy a

nd

typ

es o

f C

V e

nd

po

ints

in

pre

para

tio

n f

or

a lo

ng

er-t

erm

tria

l

-- I

G h

ad m

ean

Hb

A1

c o

f 7

.1%

, 2

.1%

low

er t

han

SG

pts

an

d m

ain

tain

ed th

is

dif

fere

nce

for

the 2

7 m

on

ths

of

foll

ow

-up

(p<

0.0

01

).

-- M

ild

an

d m

od

era

te h

yp

og

lyce

mic

ev

ents

occ

urr

ed m

ore

fre

qu

entl

y i

n t

he

IG (

16

.5

even

ts p

er p

atie

nt

per

year

vs.

1.5

ev

ents

per

pat

ien

t p

er

year

, p

<0

.00

1);

sev

ere

hy

po

gly

cem

ic e

ven

ts w

ere

rare

an

d n

ot

sig

nif

ican

tly

dif

fere

nt

bet

wee

n t

he g

rou

ps.

-- G

rou

ps

wer

e n

ot

sig

nif

ican

tly

dif

fere

nt

in b

ase

lin

e B

MI,

ser

um

TG

lev

els

, to

tal

cho

lest

ero

l/L

DL

/HD

L l

evels

, b

loo

d

pre

ssu

re a

nd

cig

are

tte

smo

kin

g (

bu

t all

4

pip

e sm

ok

ers

wer

e ra

nd

om

ized

in

to t

he I

G

arm

).

-- 6

1 C

V e

ven

ts o

ccu

rred

du

rin

g t

he s

tud

y;

33

occ

urr

ed i

n 2

4 p

ts i

n t

he I

G;

26

ev

ents

occ

urr

ed i

n 1

6 p

ts i

n t

he S

G (

p=

0.1

0);

10

pts

die

d d

uri

ng

th

e st

ud

y (

5 i

n e

ach

gro

up

,

wit

h 3

in

each

gro

up

bei

ng

CV

rel

ated

).

-- M

ult

ivari

ate

anal

ysi

s o

n t

imes

to

CV

even

t sh

ow

ed t

hat

the

on

ly s

ign

ific

ant

pre

dic

tor

vari

able

was

a p

rev

iou

s h

isto

ry

of

CV

dis

ease

(p

=0

.04

); lo

wer

Hb

A1

c

lev

el

was

a b

ord

erl

ine

corr

ela

te w

hen

sub

stit

ute

d f

or

the

trea

tmen

t as

sig

nm

ent

var

iab

le.

-- W

hen

sil

ent

base

lin

e C

V a

bn

orm

alit

ies

wer

e co

mb

ined

wit

h k

no

wn

pre

vio

us

CV

even

ts a

s th

e d

epen

den

t v

aria

ble

, o

nly

th

e

Hb

A1

c le

vel

(lo

wer

lev

el)

rose

to

sig

nif

ican

ce a

s a

pre

dic

tor

of

new

CV

even

ts (

p=

0.0

5).

-- A

uth

ors

sta

te t

hat

inte

nsi

ve

insu

lin

tre

atm

ent

des

ign

ed t

o l

ow

er

Hb

A1

c l

evel

s can

su

stai

n a

clin

ical

ly s

ign

ific

ant

sep

ara

tio

n i

n H

bA

1c

lev

els

wit

ho

ut

incr

easi

ng

BP

, d

ysl

ipid

emia

,

sev

ere

hy

po

gly

cem

ia,

excess

ive

wei

gh

t g

ain

or

hig

h i

nsu

lin

req

uir

emen

t.

-- S

mal

l sa

mp

le s

ize,

sh

ort

-du

rati

on

stu

dy

no

ted

mo

rtali

ty r

ates

near

ly i

den

tical

bet

ween

gro

up

s.

-- C

V h

isto

ry h

ad a

sig

nif

ican

t eff

ect

on

ris

k o

f

new

ev

ents

.

-- B

ord

erli

ne

tren

d t

ow

ard

mo

re C

V e

ven

ts i

n

pat

ien

ts w

ith

lo

wer

Hb

A1

c le

vel

s, b

ut

fin

din

g

nee

ds

cau

tio

us

inte

rpre

tati

on

du

e to

th

e s

ho

rt

len

gth

of

the

stu

dy

; in

suli

n d

ose

its

elf

did

no

t

app

ear

to b

e a

sig

nif

ican

t p

red

icto

r o

f ev

ents

.

-- N

eed

fu

rth

er

pro

spect

ive

stu

dy

befo

re

reco

mm

end

atio

ns

for

NID

DM

tre

atm

ent

can

be

mad

e.

-- A

uth

ors

sta

te t

hat

ben

efit

of

Hb

A1

c le

vels

bel

ow

8%

may

be

rela

tiv

ely

sm

all

.



www.icsi.org

82

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al

-ity

(+,–

,ø)

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e, c

on

fid

ence

inte

rval

, re

lati

ve

risk

,

od

ds

rati

o,

lik

elih

oo

d r

ati

o,

nu

mb

er n

eed

ed

to t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Ger

stei

n,

et a

l.,

20

08

(T

he

AC

CO

RD

Wo

rk-

gro

up

)

RC

T

A

+

-10

,25

1 p

atie

nts

wit

h a

med

ian

bas

elin

e A

1c

of

8.1

% w

ho

had

hea

rt d

isea

se o

r ev

iden

ce

of

ath

ero

scle

rosi

s, a

lbu

nie

ria,

hy

per

ten

sio

n,

left

ven

tric

le

hy

per

tro

ph

y o

r tw

o

card

iov

asc

ula

r d

isease

ris

k

fact

ors

- P

art

icip

ants

wer

e ra

nd

om

ized

to r

ecei

ve

eith

er i

nte

nsi

ve

ther

apy

tar

get

ing

red

uct

ion

of

A1

c to

bel

ow

6 o

r st

and

ard

ther

apy

tar

get

ing

A1

c b

etw

een

7.0

-7.9

-In

clu

sio

n/e

xclu

sio

n c

rite

ria

clea

rly

def

ined

-Use

d i

nte

nti

on

to

tre

at

analy

sis

- P

rim

ary

ou

tco

mes

meas

ure

d w

as a

co

mp

osi

te

of

no

n-f

ata

l m

yo

card

ial

infa

rcti

on

, n

on-f

atal

stro

ke,

an

d d

eat

h f

rom

car

dio

vas

cula

r d

iseas

e.

- O

ver

3.5

yea

rs o

f fo

llo

w-u

p,

the

pri

mar

y

ou

tco

me

occu

rred

in

35

2 i

n t

he i

nte

nsi

ve t

hera

py

gro

up

an

d 3

71

in

th

e s

tan

dard

th

erap

y g

rou

p (

RR

0.9

0, 9

5%

CI

0.7

4-1

.04

, p

=0

.16

).

- T

here

were

25

7 d

eat

hs

in t

he

inte

nsi

ve

ther

apy

gro

up

co

mp

ared

to

20

3 d

eath

s in

th

e st

and

ard

ther

apy

gro

up

(R

R =

1.2

2, 9

5%

CI

1.0

1-1

.46

,

p=

0.0

4).

- In

ad

dit

ion

, h

yp

og

lyce

mia

req

uir

ing

att

enti

on

and

weig

ht

gain

in

ex

cess

of

10

kg

occu

rred

mo

re

freq

uen

tly

in

th

e in

ten

siv

e th

erap

y g

rou

p.

- C

om

pare

d t

o s

tan

dar

d t

hera

py

, in

ten

siv

e

ther

apy

led

to

in

cre

ase

d m

ort

alit

y a

nd

did

no

t

sig

nif

ican

tly

red

uce

card

iov

asc

ula

r ev

ents

.

- D

iffe

ren

ces

in m

ort

ali

ty e

mer

ged

1-

2 y

ear

s

afte

r ra

nd

om

izati

on

, w

hic

h m

ay i

nd

icat

e th

at

the

po

ten

tial

ben

efit

s o

f in

ten

siv

e th

erap

y d

o

no

t em

erg

e fo

r se

ver

al y

ear

s, d

uri

ng

wh

ich

tim

e

ther

e is

in

cre

ase

d r

isk

of

mo

rtali

ty.

-Th

e st

and

ard

th

era

py

gro

up

had

few

er v

isit

s

and

use

d f

ewer

dru

gs

in f

ewer

com

bin

ati

on

s;

thu

s, t

he

hig

her

rat

e o

f m

ort

ali

ty i

n t

he

inte

nsi

ve t

her

apy

gro

up

may

be

rela

ted

to

th

e

var

iou

s st

rate

gie

s o

f in

ten

siv

e tr

eatm

ent.

Pat

el,

et

al.,

20

08

(AD

V-

AN

CE

tria

l)

RC

T

A

+

-11

,40

0 p

atie

nts

wit

h t

yp

e 2

dia

bete

s w

ho

wer

e d

iag

no

sed

afte

r ag

e 3

0 o

r w

ere

ov

er

55

and

had

a h

isto

ry

mic

rov

ascu

lar

or

macr

ov

asc

ula

r

dis

ease

or

at l

east

on

e

card

iov

asc

ula

r ri

sk f

acto

r

- R

and

om

ized

to

sta

nd

ard

glu

cose

co

ntr

ol

or

inte

nsi

ve

ther

apy

tar

get

ing

<6

.5%

A1

c

- P

rim

ary

ou

tco

mes

wer

e a

com

po

site

of

mic

rov

ascu

lar

even

ts (

new

or

wo

rsen

ing

nep

hro

pat

hy

, n

eed

fo

r re

nal

rep

lacem

ent

thera

py

,

or

deat

h t

o r

enal

dis

ease

) an

d a

co

mp

osi

te o

f

mac

rov

asc

ula

r ev

ents

(n

on-f

ata

l m

yo

card

ial

infa

rcti

on

, n

on

-fata

l st

rok

e, a

nd

card

iov

asc

ula

r

dis

ease

deat

h).

- O

ver

5 y

ears

of

foll

ow

-up

, A

1c

was

lo

wer

in

the

inte

nsi

ve

ther

apy

gro

up

(6

.5%

) co

mp

ared

to

the

stan

dar

d g

luco

se c

on

tro

l g

rou

p (

7.3

%).

- In

ten

siv

e c

on

tro

l re

du

ced

th

e in

cid

ence

of

com

bin

ed m

icro

- an

d m

acro

vasc

ula

r ev

ents

(18

.1%

vs.

20

.0%

wit

h s

tan

dar

d c

on

tro

l, h

azard

rati

o 0

.90

[0

.82

-0.9

8])

.

- A

red

uct

ion

in

mic

rov

ascu

lar

even

ts w

as

ob

serv

ed i

n t

he

inte

nsi

ve

trea

tmen

t g

rou

p (

9.4

%)

com

par

ed t

o t

he

stan

dar

d c

on

tro

l g

rou

p (

10

.9%

)

wit

h a

hazar

d r

ati

on

of

0.8

6 (

0.7

7-0

.97

).

- N

o r

edu

cti

on

in

macr

ov

ascu

lar

even

ts w

as

ob

serv

ed,

(haza

rd r

atio

0.9

4 [

0.8

4-1

.06

]).

- T

he o

bse

rved

10

% r

ela

tiv

e re

du

cti

on

may

be

du

e to

a r

edu

cti

on

in

wo

rsen

ing

nep

hro

pat

hy

.

- In

th

e A

DV

AN

CE

tri

al,

no

su

bg

rou

p o

f

par

ticip

ants

was

iden

tifi

ed t

o h

ave e

vid

ence

of

an a

dv

erse

eff

ect

of

inte

nsi

ve g

luco

se l

ow

erin

g

on

maj

or

vasc

ula

r o

utc

om

es,

in

clu

din

g a

sub

gro

up

wit

h a

n i

nit

ial

med

ian

A1

c

com

par

able

to

th

e A

CC

OR

D s

tud

y p

op

ula

tio

n.

- In

ten

siv

e t

hera

py

sig

nif

ican

tly

red

uce

d t

he

pri

mary

co

mp

osi

te o

utc

om

e o

f m

ajo

r

mac

rov

asc

ula

r o

r m

icro

vasc

ula

r ev

ents

. T

her

e

was

no

sep

ara

te s

ign

ific

ant

red

uct

ion

in

maj

or

mac

rov

asc

ula

r ev

ents

, alt

ho

ug

h t

his

ben

efi

t

cou

ld n

ot

be r

ule

d o

ut.



www.icsi.org

83

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al-

ity

(+

,–

,ø)

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s

(e.g

., p

-val

ue,

co

nfi

den

ce i

nte

rval,

rela

tiv

e ri

sk,

od

ds

rati

o, li

keli

ho

od

rati

o, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Bre

tzel

,

et a

l.,

20

08

RC

T

A

+

- 5

15

ran

do

mly

assi

gn

ed t

o i

nsu

lin

lisp

ro o

r in

suli

n

gla

rgin

e

- B

asel

ine

A1

c

bet

wee

n 7

.5%

an

d

10

.5%

, B

MI

35

or

less

- P

rim

ary

en

dp

oin

ts w

ere

chan

ges

in

A1

c

and

blo

od

glu

cose

at

44

week

s fo

llo

w-u

p

- C

han

ges

in A

1c i

n t

he g

larg

ine g

rou

p

wer

e 8

.7 t

o 7

.0 a

nd

8.7

to

6.8

in

lis

pro

gro

up

.

- 5

7%

of

pati

ents

in

th

e g

larg

ine g

rou

p

and

69

% i

n t

he

lisp

ro g

rou

p r

eac

hed

A1

c

bel

ow

7%

.

- F

all

in

mean

fas

tin

g b

loo

d g

luco

se w

as

4.3

in

th

e g

larg

ine

gro

up

an

d -

1.8

in

th

e

lisp

ro g

rou

p (

p <

0.0

00

1).

- In

cid

ence

of

hy

peg

lycem

ic e

ven

ts w

as

less

in

th

e g

larg

ine g

rou

p c

om

pare

d t

o

lisp

ro g

rou

p.

- M

ean

weig

ht

gain

s w

ere

3.0

1 i

n t

he

gla

rgin

e g

rou

p a

nd

3.5

4 i

n t

he

lisp

ro

gro

up

.

- T

he t

wo

tre

atm

ents

were

eq

ual

ly e

ffect

ive

in l

ow

erin

g

A1

c.

[No

te t

ha

t th

is s

tud

y p

rob

ab

ly d

oes

no

t h

ave

lo

ng

en

ou

gh

foll

ow

-up

tim

e to

det

ect

an

y a

dver

se e

ven

ts.

In

ad

dit

ion

,

pa

tien

ts r

ecru

ited

fo

r th

is s

tud

y d

id n

ot

ha

ve e

xis

tin

g

card

iova

scu

lar

dis

ease

or

risk

fa

cto

rs a

t b

ase

lin

e, u

nli

ke

AC

CO

RD

an

d A

DV

AN

CE

pa

tien

ts.]



www.icsi.org

84

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al-

ity

(+,–

,ø)

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s

(e.g

., p

-val

ue,

co

nfi

den

ce i

nte

rval,

rela

tiv

e ri

sk,

od

ds

rati

o, li

keli

ho

od

rati

o, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Ho

lman

,

et a

l.,

20

08

RC

T

[Th

is i

s a

lo

ng

-

term

fo

llo

w-u

p o

f

pa

rtic

ipa

nts

po

st-

inte

rven

tio

n,

du

rin

g w

hic

h t

ime

pa

rtic

ipa

nts

were

no

t in

terv

ened

on

no

r w

ere

th

ey

enco

ura

ged

to

ma

inta

in t

heir

trea

tmen

t

ass

ign

men

t.]

A

+

- O

ut

of

a tr

ial

of

4,2

09

new

ly

dia

gn

ose

d d

iab

etic

pat

ien

ts r

and

om

ly

assi

gn

ed t

o

con

ven

tio

nal

ther

apy

or

inte

nsi

ve

thera

py

,

3,2

77

wer

e av

aila

ble

for

po

st-t

rial

ob

serv

atio

n.

- D

iffe

ren

ces

in A

1c

du

e to

tre

atm

ent

gro

up

wer

e

dim

inis

hed

by

th

e

end

of

the

1-y

ear

tria

l, a

t th

e s

tart

of

po

st-t

rial

fo

llo

w-u

p

the

med

ian

A1

c w

as

7.9

in

th

e

sulf

on

ylu

rea

trea

tmen

t g

rou

p, 8

.5

in t

he c

om

par

iso

n

gro

up

an

d 8

.4 i

n t

he

met

form

in t

reat

men

t

gro

up

, 8

.9 i

n t

he

com

par

iso

n g

rou

p.

- O

utc

om

es

of

inte

rest

were

an

y d

iab

etes

rela

ted

en

d p

oin

t, d

iab

etes-

rela

ted

dea

th,

dea

th f

rom

an

y c

ause

, M

I, s

tro

ke,

per

iph

eral

vas

cula

r d

isea

se, m

icro

vasc

ula

r d

isease

.

- In

th

e s

ulf

on

ylu

rea

arm

, co

mp

are

d t

o t

he

con

ven

tio

nal

ther

apy

gro

up, th

e R

R (

95

%

CI)

of

dia

bete

s-re

late

d e

nd

pt

0.9

1 (

0.8

3-

0.9

9),

dia

bet

es-

rela

ted

deat

h 0

.83

(0

.73

-

0.9

6),

deat

h f

rom

an

y c

ause

0.8

7 (

0.7

9-

0.9

6),

MI

0.8

5 (

0.7

4-0

.97

), s

tro

ke

0.9

1

(0.7

3-1

.13

), P

VD

0.8

2 (

0.5

6-1

.19

),

mic

rov

ascu

lar

dis

eas

e 0

.76

(0

.64-0

.89

).

- In

th

e m

etf

orm

in a

rm,

com

pare

d t

o t

he

con

ven

tio

nal

ther

apy

gro

up, th

e R

R (

95

%

CI)

of

dia

bete

s-re

late

d e

nd

pt

was

0.7

9

(0.6

6-0

.95

), d

iab

etes

-rel

ated

dea

th 0

.70

(0.5

3-0

.92

), d

eath

fro

m a

ny

cau

se 0

.73

(0.5

9-0

.89

), M

I 0

.67

(0

.51-0

.89

), s

tro

ke

0.8

0 (

0.5

0-1

.27

), P

VD

0.6

3 (

0.3

2-1

.27

),

mic

rov

ascu

lar

dis

eas

e 0

.84

(0

.60-1

.17

).

- B

enef

its

of

inte

nsi

ve t

hera

py

to

co

ntr

ol g

luco

se w

ere

mai

nta

ined

fo

r u

p t

o 1

0 y

ears

aft

er

the

cess

ati

on

of

the

ran

do

miz

ed t

rial.

- In

th

e s

ulf

on

ylu

rea

gro

up, th

e r

edu

cti

on

in

mic

rov

ascu

lar

dis

eas

e ri

sk a

nd

dia

bet

es-r

elat

ed

end

po

int

risk

ob

serv

ed i

n t

he i

nte

nsi

ve

thera

py

gro

up

was

su

stai

ned

th

rou

gh

ou

t th

e p

ost

-tri

al p

erio

d, d

esp

ite

rap

id c

on

ver

gen

ce

of

A1

c v

alu

es a

nd

sim

ilar

use

of

glu

cose

-lo

wer

ing

th

era

pie

s.

In t

he m

etfo

rmin

gro

up

, m

ade

up

of

ov

erw

eig

ht

pat

ien

ts,

risk

red

ucti

on

s fo

r M

I an

d a

ll-c

ause

mo

rtali

ty

wer

e su

stain

ed t

hro

ug

ho

ut

the

po

st-t

rial

peri

od

des

pit

e

sim

ilar

A1

c le

vel

s b

etw

een

tre

atm

ent

and

co

ntr

ol

gro

up

.

[No

te:

Th

is r

epo

rt d

oes

no

t in

dic

ate

wh

at

the

targ

et

A1

c le

vel

s w

ere

fo

r th

e in

terv

enti

on

stu

dy,

no

r w

ha

t

A1

cs w

ere a

chie

ved

wit

h i

nte

nsi

ve t

her

ap

y d

uri

ng

th

e

tria

l.

At

the b

egin

nin

g o

f p

ost

-tri

al

foll

ow

-up

, th

e

med

ian

A1

cs

wer

e a

rou

nd

8.]

[No

te:

Pa

rtic

ipa

nts

were

excl

ud

ed f

rom

th

e st

ud

y i

f

they

ha

d M

I w

ith

in o

ne

yea

r, c

urr

ent

an

gin

a o

r h

eart

fail

ure

, m

ore

th

an

on

e m

ajo

r va

scu

lar

even

t,

ma

lig

na

nt

hyp

ert

ensi

on

, u

nco

rrec

ted

en

do

crin

e

dis

ord

er,

ret

ino

pa

thy

req

uir

e l

ase

r tr

eatm

ent,

ele

vate

d

seru

m c

rea

tin

ine

level

, ke

ton

uri

a.

So

, th

ese

pa

tien

ts

did

no

t h

ave

exi

stin

g v

asc

ula

r d

isea

se o

r ri

sk f

acto

rs,

un

like

AC

CO

RD

an

d A

DV

AN

CE

.]



www.icsi.org

85

Au

tho

r/Y

ear

D

esig

n

Ty

pe

Cla

ss

Qu

alit

y (

+,–

,ø)

Po

pu

lati

on

Stu

die

d/S

amp

le

Siz

e

Pri

mar

y O

utc

om

e M

eas

ure

(s)/

Res

ult

s

(e.g

., p

-val

ue,

co

nfi

den

ce i

nte

rval,

rela

tiv

e ri

sk,

od

ds

rati

o, li

keli

ho

od

rati

o, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Du

ckw

ort

h,

et

al.,

20

09

RC

T

A

Ø

1,7

91

mil

itary

vet

era

ns

(mea

n a

ge

60

.4 y

ears

) w

ho

had

a

sub

op

tim

al

resp

on

se

to t

hera

py

fo

r ty

pe

2

dia

bete

s w

ere

ran

do

miz

ed t

o r

ece

ive

eith

er i

nte

nsi

ve

or

stan

dar

d g

luco

se

con

tro

l. F

ort

y p

erc

ent

of

these

pati

ents

had

alre

ady

had

a

card

iov

asc

ula

r ev

ent.

Th

e g

oal

of

the

inte

rven

tio

n w

as

an

abso

lute

red

uct

ion

in

A1

c o

f 1

.5 p

erc

enta

ge

po

ints

.

Pat

ien

ts i

n i

nte

nsi

ve

ther

apy

gro

up

were

star

ted

on

max

imu

m

do

ses,

an

d p

atie

nts

in

the

stan

dar

d t

hera

py

gro

up

wer

e st

arte

d o

n

hal

f th

e m

axim

al

do

ses

of

metf

orm

in

plu

s ro

sig

lita

zon

e (i

f

BM

I >

27

kg

/m2)

or

gli

mep

irid

e p

lus

rosi

gli

tazo

ne

(if

BM

I

< 2

7 k

g/

m2).

Th

e p

rim

ary

en

d p

oin

t in

th

is s

tud

y w

as

tim

e

fro

m r

and

om

izat

ion

to

th

e fi

rst

occu

rren

ce o

f

a m

ajo

r ca

rdio

vasc

ula

r ev

ent,

a c

om

po

site

of

MI,

str

ok

e, d

eat

h f

rom

CV

D c

ause

s,

con

ges

tiv

e h

ear

t fa

ilu

re,

surg

ery

fo

r v

asc

ula

r

dis

ease

, in

op

era

ble

co

ron

ary

dis

ease

or

amp

uta

tio

n.

Aft

er a

med

ian

fo

llo

w-u

p 5

.6 y

ear

s, m

edia

n

A1

c le

vels

were

8.4

% i

n t

he

stan

dar

d t

hera

py

gro

up

an

d 6

.9%

in

th

e i

nte

nsi

ve

thera

py

gro

up

. T

he

pri

mar

y o

utc

om

e o

ccu

rred

in

26

4

of

stan

dard

th

erap

y g

rou

p p

atie

nts

an

d 2

35

of

inte

nsi

ve t

her

apy

gro

up

pat

ien

ts (

Haz

ard

rat

io

= 0

.88

95

% C

I 0

.74

-1.0

5).

T

here

was

also

no

sig

nif

ican

t d

iffe

ren

ce

betw

een

gro

up

s w

ith

reg

ard

to

th

e c

om

po

site

ou

tco

me.

Th

e au

tho

rs c

on

clu

de

that

in

ten

siv

e g

luco

se

con

tro

l in

pat

ien

ts w

ith

po

orl

y c

on

tro

lled

ty

pe 2

dia

bete

s h

ad n

o s

ign

ific

ant

effe

cts

on

th

e r

ates

of

majo

r car

dio

vas

cula

r ev

ents

, d

eat

h o

r

mic

rov

ascu

lar

com

pli

cati

on

s.

An

ob

vio

us

lim

itat

ion

of

this

stu

dy

is

that

the

po

pu

lati

on

was

pre

do

min

antl

y m

en,

so

extr

apo

lati

on

of

thes

e fi

nd

ing

s to

wo

men

sho

uld

be

do

ne

wit

h c

auti

on

. A

dd

itio

nal

ly,

at

the

beg

inn

ing

of

the

stu

dy

(2

00

0-2

00

3),

th

e

avai

lab

ilit

y o

f n

ew d

rug

s w

as

lim

ited

, so

it

rem

ain

s p

oss

ible

th

at

new

er

agen

ts m

ay h

ave

dif

fere

nt

eff

ects

.

Th

e au

tho

rs n

ote

th

at

adv

erse

ev

ents

wer

e m

ore

com

mo

n i

n t

he

inte

nsi

ve

ther

apy

gro

up;

ho

wev

er,

ther

e w

as n

o d

iffe

ren

ce

in C

VD

dea

th

bet

wee

n g

rou

ps.

[No

te:

Wh

ile

the

au

tho

rs s

ug

ges

t th

at

thei

r

resu

lts

are

co

nsi

sten

t w

ith

th

e A

DV

AN

CE

an

d

AC

CO

RD

tri

als

, it

is

no

t a

va

lid

co

mp

ari

son.

Th

eir

fin

din

g t

ha

t th

ere

wa

s n

o d

iffe

ren

ce

in

CV

D d

eath

ra

tes

is l

ikel

y d

ue t

o l

ack

of

po

wer

to d

etect

su

ch d

iffe

ren

ces

(or

lack

there

of)

.]



www.icsi.org

86

Conclusion Grading Worksheet C – Annotations #13, 14 (Statin Use)


Wo

rk

Gro

up

's C

on

clu

sio

n:

Fo

r p

atie

nts

wit

h t

yp

e 2

dia

bet

es m

elli

tus,

co

nsi

der

th

e u

se o

f a

stat

in.

Ran

do

miz

ed c

on

tro

lled

tr

ials

, in

clu

din

g s

om

e la

rge

tria

ls,

and

ob

serv

atio

nal

dat

a co

nsi

sten

tly

sh

ow

a b

enef

it o

f st

atin

th

erap

y f

or

pati

ents

wit

h t

yp

e 2

d

iab

etes

. S

om

e st

ud

ies

also

rep

ort

ed t

hat

sta

tin

th

erap

y w

as w

ell

tole

rate

d i

n t

hes

e p

atie

nts

. H

ow

ever

, n

on

e o

f th

ese

stu

die

s w

as a

ble

to

ass

ess

lon

g-t

erm

eff

ects

of

stat

in t

reat

men

t/u

se.

Co

nclu

sio

n G

ra

de:

I

Au

tho

r/

Yea

r D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

ra

tio

, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Co

lho

un

, et

al.

, C

AR

DS

20

04

RC

T

A

+

2,8

38

pat

ien

ts (

age

40-7

5 y

ear

s, 9

4%

C

auca

sio

n a

nd

68

% m

ale

), i

n 1

32

cen

ters

in

th

e U

K/I

rela

nd

Ato

rva

sta

tin

10

mg

vs.

pla

ceb

o

Acu

te c

oro

nar

y e

ven

t H

R 0

.63

(0

.48-0

.83

) S

tro

ke

HR

0.5

2 (

0.3

1-0

.89

)

Dea

th f

rom

an

y c

ause

HR

0.7

3 (

0.5

2-0

.85

)

Ran

do

miz

atio

n w

ith

eq

ual

gro

up

s at

bas

eli

ne a

nd

1%

lo

st t

o f

oll

ow

-up

af-

ter

a m

ean

fo

llo

w-u

p o

f 4

year

s.

An

aly

sis

was

wit

h i

nte

nti

on

to

tre

at,

and

du

rin

g t

he

cou

rse

of

stu

dy

, 9

% o

f p

laceb

o g

rou

p w

as k

no

wn

to

tak

e a

stati

n a

nd

85

% o

f th

e in

terv

enti

on

(ei

-th

er a

torv

asta

tin

or

ano

ther

sta

tin

).

Ov

eral

l fr

equ

ency

of

adv

erse

ev

ents

o

r se

rio

us

adv

erse

ev

ents

did

no

t d

if-

fer

betw

een

tre

atm

ents

. I

n e

ach

g

rou

p, 1

.1%

of

pat

ien

ts r

and

om

ized

h

ad o

ne

or

mo

re s

erio

us

adv

erse

ev

ents

. B

ased

on

pre

- an

d p

ost

-LD

L

val

ues

in

in

terv

enti

on

an

d c

on

tro

l g

rou

p, th

ere d

id n

ot

app

ear

to b

e a

par

ticu

lar

thre

sho

ld l

evel

of

LD

L c

ho

-

lest

ero

l to

red

uce

card

iov

ascu

lar

even

ts.

Ro

bin

s, e

t al

., 2

00

1

RC

T

A

+

2,5

31

men

wit

h c

oro

nar

y h

eart

dis

eas

e

and

lo

w H

DL

-C l

evel

s (a

vg

32

mg

/dL

).

62

0 p

atie

nts

had

dia

bet

es.

Gem

fib

rizo

l 1

,20

0 m

gm

/da

y v

s. p

lace

bo

RR

95

% C

I (4

-46

%)

Pat

ien

ts w

ere r

and

om

ized

wit

h c

on

-ce

ale

d a

llo

cati

on

; th

ey w

ere s

imil

ar a

t b

aseli

ne a

nd

tre

ated

rel

ativ

ely

sim

i-la

rly

th

rou

gh

ou

t th

e tr

ial;

pat

ien

ts,

stu

dy

per

son

nel,

hea

lth

car

e p

rov

ider

s

and

ou

tco

mes

ass

esso

rs w

ere

bli

nd

ed;

inte

nti

on

-to

-tre

at a

naly

sis

was

con

-d

uct

ed;

ther

e w

as t

riv

ial

loss

to

fol-

low

-up

. N

o v

alid

ity

con

cern

s.

Upd

ated

Thi

rteen

th E

ditio

n, M

ay 2

009.


www.icsi.org

87

Conclusion Grading Worksheet C – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Statin) Thirteenth Edition/May 2009

Au

tho

r/Y

ear

Des

ign

T

yp

e C

lass

Q

ual

-it

y

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

ra

tio

, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Hea

rt

Pro

tec-

tio

n,

20

02

RC

T

A

+

20

,53

6 p

atie

nts

40

-80

yea

rs (

75

%

mal

es, 3

5%

wit

ho

ut

a p

rio

r h

isto

ry o

f C

AD

, 2

8%

>7

0 y

ear

s o

f ag

e) w

ith

no

n-

fast

ing

LD

L c

ho

l o

f >

3.4

mm

ol/

L (

13

5

mg

m%

). 3

,98

2 p

atie

nts

had

dia

bete

s,

3,9

82

wit

ho

ut

pri

or

hx

of

MI

or

CA

D.

Sim

va

sta

tin

40

mg

m/d

ay

vs.

pla

ceb

o

Maj

or

vas

cula

r ev

ent

Nu

mb

er n

eed

ed t

o t

reat

2

1 9

5%

CI

(14-4

1)

Ran

do

miz

atio

n i

ncl

ud

ed i

nd

ivid

uals

fe

lt n

ot

to h

ave

a cl

ear

cli

nic

al i

nd

ica-

tio

n f

or

the u

se o

f a s

tati

n.

Cen

tral

tele

ph

on

e ra

nd

om

izati

on

(p

resu

med

co

nce

aled

ass

ign

men

t) w

ith

min

imi-

zati

on

alg

ori

thm

to

bal

ance

trea

tmen

t g

rou

ps.

M

ean

du

rati

on

of

foll

ow

-up

w

as 5

yea

rs w

ith

at

leas

t 8

0%

dem

on

-st

rati

ng

co

mp

lian

ce w

ith

use

of

sim

-v

asta

tin

or

pla

ceb

o.

4,0

02

pati

ents

too

k a

no

n-s

tud

y s

tati

n t

o i

ncl

ud

e th

e p

laceb

o a

rm (

aver

age

of

17

% f

or

5

yea

rs).

A

ll p

ati

ents

wer

e ac

cou

nte

d

for

(lo

ss t

o f

oll

ow

-up

0.0

3-0

.33

%)

wit

h i

nte

nti

on

-to

-tre

at

analy

sis.

P

a-ti

ents

, p

rov

ider

s an

d o

utc

om

e as

ses-

sors

wer

e b

lin

ded

to

tre

atm

ent

arm

s,

and

in

terv

enti

on

an

d c

on

tro

l g

rou

p

wer

e si

mil

ar a

t st

art

of

tria

l.

Oth

er

than

th

e in

terv

enti

on

, it

is

no

t p

oss

ible

to

tel

l if

gro

up

s w

ere t

reate

d e

qu

ally

.

Set

ter-

gre

n, et

al.,

20

08

RC

T

A

- 4

3 p

atie

nts

wit

h t

yp

e 2

dia

bete

s o

r im

-p

aire

d g

luco

se t

ole

ran

ce

and

sta

ble

co

ron

ary

art

ery

dis

eas

e w

ere

recr

uit

ed

and

ran

do

miz

ed. P

ati

ents

wh

o w

ere

on

a

stati

n o

r o

ther

lip

id-l

ow

erin

g t

reat

men

t in

th

e p

rev

iou

s 1

2 w

eek

s w

ere

excl

ud

ed.

Pat

ien

ts w

ere r

and

om

ized

to

eit

her

sim

-v

asta

tin

80

mg

/d o

r ez

etim

ibe 1

0 m

g/d

p

lus

sim

vast

atin

10

mg

/d f

or

6 w

eek

s.

4 p

atie

nts

wer

e l

ost

to

fo

llo

w-u

p (

2 f

rom

ea

ch a

rm)

and

on

ly 3

9 w

ere

analy

zed

.

Th

e p

rim

ary

ou

tco

mes

of

this

stu

dy

were

en

do

the-

lia

l fu

nct

ion

mea

sured

by

bra

chia

l a

rtery

flo

w-

med

iate

d v

aso

dil

ati

on

s a

nd

th

e ef

fect

s o

f en

do

theli

n

recep

tor b

lock

ag

e, se

rum

lip

ids,

an

d i

nfl

am

ma

tory

ma

rker

s w

ere

ev

alu

ate

d a

t b

ase

lin

e a

nd

foll

ow

-up

.

Aft

er 6

week

s o

f fo

llo

w-u

p,

LD

L c

ho

lest

ero

l le

vels

dec

reas

ed f

rom

3.1

to

1.5

mm

ol/

L a

nd

3.0

to

1.3

m

mo

l/L

in

th

e s

imv

ast

atin

an

d s

imv

asta

tin

plu

s ez

eti

mib

e g

rou

ps,

res

pecti

vely

(p

=).

T

he

chan

ges

in

fl

ow

med

iate

d d

ilati

on

an

d C

RP

wer

e n

ot

dif

fere

nt

be-

tween

gro

up

s; i

n t

he

enti

re s

tud

y g

rou

p, fl

ow

med

iate

d

dil

ati

on

in

crea

sed

fro

m 4

.3%

to

5.5

%,

and

CR

P d

e-cr

ease

d f

rom

3.1

to

2.3

mg

/L.

Th

e au

tho

rs c

on

clu

de

that

th

e tw

o

trea

tmen

ts d

id n

ot

dif

fer

wit

h r

egar

d

to t

hei

r ef

fect

on

en

do

thel

ial

functi

on

in

pati

ents

wit

h t

yp

e 2

dia

bet

es,

im-

pai

red

glu

cose

to

lera

nce

and

sta

ble

co

ron

ary

art

ery

dis

eas

e.

Th

ey f

urt

her

p

osi

t th

at

in c

on

tras

t to

th

eir

hy

po

the-

sis,

th

e li

pid

-lo

wer

ing

eff

ects

of

stat

-in

s w

ere

mo

re i

mp

ort

ant

for

end

oth

e-li

al f

un

ctio

n a

s o

pp

ose

d t

o t

he

ple

i-o

tro

pic

eff

ect

s o

f st

atin

s.

[No

te:

Th

e i

nve

stig

ato

rs d

id n

ot

ad

-h

ere

to i

nte

nti

on

-to

-tre

at

an

aly

sis

pri

ncip

les.

T

here

wer

e s

om

e p

ote

n-

tia

lly

imp

ort

an

t d

iffe

ren

ces

in A

1c,

asp

irin

use

, a

s w

ell

as

use

of

bet

a-

blo

cker

s a

nd

ca

lciu

m c

ha

nn

el

blo

ck-

ers

bet

wee

n t

rea

tmen

t g

rou

ps

at

ba

se-

lin

e.]


www.icsi.org

88


Au

tho

r/Y

ear

Des

ign

T

yp

e C

lass

Q

ual

-it

y

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

ra

tio

, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Fle

g,

et

al.,

20

08

D

ata

fro

m t

he

SA

ND

S

tria

l

No

n-

ran

do

m-

ized

tri

al

C

Ø

Sec

on

dar

y a

naly

sis

of

data

fro

m t

he

Sto

p A

ther

osc

lero

sis

in N

ativ

e D

iab

eti

cs

Stu

dy

(S

AN

DS

) T

rial

. A

gg

ress

ively

trea

ted

pati

ents

(n

=6

9)

tak

ing

sta

tin

s p

lus

eze

tim

ibe

wer

e c

om

par

ed t

o a

g-

gre

ssiv

ely

tre

ated

pati

ents

on

sta

tin

s al

on

e (

n=

15

4)

and

no

n-a

gg

ress

ively

tr

eate

d p

ati

ents

(n

=2

04

).

Th

e p

rim

ary

ou

tco

mes

of

this

stu

dy

were

ch

an

ge i

n

L

DL

ch

ole

stero

l a

nd

ca

roti

d i

nti

ma-m

edia

th

ick

-n

ess.

Mea

n L

DL

ch

ole

ster

ol

was

red

uce

d b

y 3

1 m

g/d

L a

nd

3

2 m

g/d

L i

n t

he a

gg

ress

ive

gro

up

rec

eiv

ing

sta

tin

s p

lus

eze

tim

ibe

ver

sus

stati

ns

alo

ne c

om

par

ed w

ith

a

chan

ge

of

1m

g/d

L i

n t

he

no

n-a

gg

ress

ive g

rou

p.

At

36

mo

nth

s fo

llo

w-u

p,

mean

car

oti

d i

nti

ma-

med

ia

reg

ress

ed f

rom

base

lin

e si

mil

arly

in

th

e e

zeti

mib

e (-

0.0

25

mm

) an

d n

on

-ezeti

mib

e (

-0.0

12

mm

) g

rou

ps

wh

ile

it p

rog

ress

ed i

n t

he n

on

-ag

gre

ssiv

e tr

eat

men

t g

rou

p (

0.0

39

).

Th

e au

tho

rs c

on

clu

de

that

am

on

g p

er-

son

s w

ith

ty

pe

2 d

iab

etes

an

d b

asel

ine

LD

L c

ho

lest

ero

l !

10

0 m

g/d

L.

Bo

th

agg

ress

ive

treat

men

t st

rate

gie

s w

ere

effe

cti

ve

at r

edu

cin

g c

aro

tid

in

tim

a-m

edia

th

ick

nes

s.

[No

te:

Th

is s

tud

y u

sed

da

ta f

rom

th

e

SA

ND

S t

ria

l fo

r a

sec

on

da

ry a

na

lysi

s th

at

com

pa

red

gro

up

s w

ith

in t

he

ag

-g

ress

ive

trea

tmen

t a

rm. T

her

efo

re,

the

stu

dy d

esig

n u

sed

fo

r th

is a

na

lysi

s

is n

ot

a r

an

do

miz

ed t

ria

l; r

ath

er,

the

da

ta a

re b

ein

g a

na

lyze

d a

s a

no

n-

ran

do

miz

ed t

ria

l o

r co

ho

rt s

tud

y.]

Fer

rer-

Gar

cia

, et

al.

, 2

00

8

No

n-

ran

do

m-

ized

, u

nco

n-

tro

lled

tr

ial

C

- 2

02

pat

ien

ts w

ith

ty

pe 2

dia

bete

s w

ho

had

no

sta

tin

use

in

th

e p

rio

r 2

4 w

eek

s.

All

met

cri

teri

a f

or

ph

arm

aco

log

ic t

her

-ap

y, acc

ord

ing

to

th

e N

CE

P-A

TP

III

an

d A

DA

cri

teri

a, w

ith

LD

L l

evels

in

ex

cess

of

2.6

mm

ol/

L.

Th

ese p

ati

ents

w

ere

assi

gn

ed t

o r

ece

ive a

dail

y d

osa

ge

of

ato

rvas

tati

n b

ased

on

th

eir

in

itia

l

LD

L c

ho

lest

ero

l le

vels

.

Th

e p

rim

ary

ou

tco

me

of

this

stu

dy

wa

s th

e p

rop

or-

tio

n o

f p

ati

ents

ach

iev

ing

th

e L

DL

ch

ole

stero

l g

oa

l a

fter

24

wee

ks

of

trea

tmen

t.

18

8 p

atie

nts

co

mp

lete

d t

he

stu

dy;

of

tho

se, 6

6.5

%

ach

iev

ed t

he L

DL

ch

ole

ster

ol

targ

et. A

t d

ose

s o

f 1

0,

20

, 4

0 a

nd

80

mg

/day

of

ato

rvas

tati

n,

the

% o

f p

atie

nts

re

ach

ing

go

al

LD

L w

as 7

5%

, 6

7%

, 5

8%

an

d 5

9%

, re

-

spec

tiv

ely

.

Th

e au

tho

rs c

on

clu

de

that

in

div

idu

al-

izin

g t

he

star

tin

g d

ose

of

atorv

ast

atin

ac

cord

ing

to

bas

eli

ne

and

tar

get

LD

L

cho

lest

ero

l le

vel

s all

ow

ed a

hig

h p

ro-

po

rtio

n o

f ty

pe

2 d

iab

ete

s p

atie

nts

to

ac

hie

ve t

he

targ

et

wit

hin

24

wee

ks.

Th

e au

tho

rs n

ote

d t

hat

they

ob

serv

ed

a re

du

cti

on

in

tri

gly

cer

ides,

bu

t n

o

chan

ge

in A

1c.

Th

is s

tud

y d

id n

ot

add

ress

lim

itati

on

s o

f h

avin

g n

o c

on

tro

l g

rou

p.

Th

ey a

lso

did

no

t ex

pla

in w

hy

th

ey d

id n

ot u

se

an i

nte

nti

on

-to

-tre

at

analy

sis

if t

his

is

a tr

ial.


www.icsi.org

89


Au

tho

r/

Yea

r D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

ra

tio

, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Leit

er,

et

al.,

20

08

T

he

AC

TF

AS

T s

tud

y

No

n-

ran

do

m-

ized

op

en

lab

el

tria

l

C

Ø

2,7

17

hig

h-r

isk

su

bje

cts

, 1

,02

4 o

f w

ho

m

had

dia

bet

es a

nd

1,2

51

had

met

abo

lic

syn

dro

me.

P

ati

ents

had

CH

D o

r C

HD

eq

uiv

ale

nt

at

bas

eli

ne

and

LD

L c

ho

les-

tero

l le

vels

bet

wee

n 1

00

an

d 2

20

m

g/d

L. P

ati

ents

wer

e as

sig

ned

a s

tart

-in

g d

ose

of

arto

vas

tati

n (

10

, 2

90

, 4

0 o

r

80

mg

/day

) b

ased

on

LD

L c

ho

lest

ero

l le

vels

an

d s

tati

n u

se a

t b

aseli

ne.

Th

e p

rim

ary

en

d p

oin

t o

f th

is s

tud

y w

as

the

pro

-p

ort

ion

of

pa

tien

ts w

ho

ach

iev

ed

LD

L c

ho

lest

ero

l g

oa

ls.

Am

on

g p

atie

nts

wit

h d

iab

ete

s, 8

1%

of

sub

ject

s w

ho

w

ere

pre

vio

usl

y n

ot

on

a s

tati

n (

82

%, 8

4%

, 8

2%

an

d

76

% w

ith

10

, 2

0, 4

0 a

nd

80

mg

/day

, re

spec

tiv

ely

)

reac

hed

th

e L

DL

ch

ole

ster

ol

targ

et.

A

mo

ng

pat

ien

ts

wh

o w

ere p

rev

iou

sly

on

a s

tati

n,

60

% o

f su

bje

cts

(6

1%

, 6

8%

an

d 4

7%

wit

h 2

0, 4

0 a

nd

80

mg

/day

, re

-sp

ecti

vely

) re

ach

ed L

DL

ch

ole

ster

ol

targ

et.

Th

e au

tho

rs c

on

clu

de

that

a t

arg

ete

d

do

se o

f ato

rvas

tati

n a

llo

ws

mo

st p

a-ti

ents

wit

h t

yp

e 2

dia

bet

es t

o a

chie

ve

thei

r L

DL

ch

ole

ster

ol

targ

et w

ith

th

e in

itia

l d

ose

or

a si

ng

le t

itra

tio

n w

ith

in

12

wee

ks.

T

he a

uth

ors

fu

rth

er c

on

-cl

ud

e t

hat

hig

her

sta

rtin

g d

ose

s o

f

stati

ns

are

ben

efic

ial

and

well

to

ler-

ated

, b

ut

low

er d

ose

s w

ork

, to

o.

Lim

itati

on

s o

f th

is s

tud

y i

ncl

ud

e th

at

it w

as n

ot

bli

nd

ed.

Ho

war

d,

et a

l.,

20

08

T

he

SA

ND

S

Tri

al

Ran

do

m-

ized

co

n-

tro

lled

tr

ial

A

+

Par

ticip

ants

wer

e 4

99

Am

eric

an I

nd

ian

men

an

d w

om

en a

ged

> 4

0 y

ear

s w

ith

ty

pe

2 d

iab

etes

an

d n

o p

rio

r ca

rdio

vas

-cu

lar

even

ts. F

oll

ow

-up

tim

e w

as

for

3

yea

rs.

Pat

ien

ts w

ere r

and

om

ized

to

ag

gre

ssiv

e

or

stan

dar

d t

reatm

ent

gro

up

s.

Th

e p

rim

ary

ob

ject

ive

of

this

stu

dy

wa

s to

co

mp

are

the

pro

gre

ssio

n o

f su

bcl

inic

al

ath

ero

scle

rosi

s in

a

du

lts

wit

h t

yp

e 2

dia

bet

es t

rea

ted

to

rea

ch a

gg

res

-si

ve t

arg

ets

of

low

-den

sity

LD

L c

ho

lest

ero

l a

nd

b

loo

d p

ress

ure.

Mea

n t

arg

et L

DL

ch

ole

ster

ol

and

sy

sto

lic

blo

od

pre

s-su

re l

evels

wer

e r

eac

hed

an

d m

ain

tain

ed i

n b

oth

gro

up

s.

Mean

(9

5%

co

nfi

den

ce i

nte

rval)

lev

els

for

LD

L c

ho

lest

ero

l at

the

end

of

foll

ow

-up

wer

e 7

2 (

69

-7

5)

and

10

4 (

10

1-1

06

) an

d S

BP

lev

els

wer

e 1

17

(1

15-

11

8)

and

12

9 (

12

8-1

30

) in

th

e ag

gre

ssiv

e v

s. s

tan

dar

d

trea

tmen

t g

rou

ps,

resp

ecti

vel

y.

Fro

m b

asel

ine t

o f

oll

ow

-up

, th

ere

wer

e g

reate

r de-

crea

ses

in c

aro

tid

in

tim

a m

edia

th

ick

nes

s, l

eft

ven

tric

u-

lar

mas

s in

dex

, an

d c

aro

tid

art

eria

l cr

oss

-sec

tio

n i

n t

he

agg

ress

ive

gro

up

co

mp

ared

to

th

e n

on-a

gg

ress

ive

gro

up

.

Ser

iou

s ad

ver

se e

ven

ts r

ela

ted

to

blo

od

pre

ssu

re m

edi-

cati

on

wer

e h

igh

er i

n t

he a

gg

ress

ive g

rou

p (

4 v

s. 1

in

no

n-a

gg

ress

ive g

rou

p).

Car

dio

vas

cula

r ev

ents

did

no

t d

iffe

r si

gn

ific

antl

y

bet

ween

gro

up

s.

Th

e au

tho

rs c

on

clu

de

that

th

e ag

gre

s-

siv

ely

tre

ate

d g

rou

p h

ad a

reg

ress

ion

o

f su

bcl

inic

al

ath

ero

scle

rosi

s (i

nti

ma

med

ia t

hic

kn

ess,

lef

t v

entr

icu

lar

mas

s in

dex

).

At

the

sam

e ti

me,

the

stan

-d

ard

tre

atm

ent

gro

up

had

a w

ors

enin

g

in i

nti

ma m

edia

th

ick

nes

s.

Th

ere w

ere n

o d

iffe

ren

ces

in

cli

nic

al

CV

D o

utc

om

es b

etw

een

gro

up

s, a

nd

th

e p

rog

ress

ion

of

sub

clin

ical

dis

eas

e

in t

he

stan

dar

d t

reatm

ent

gro

up

was

lo

wer

th

an e

xp

ect

ed.

Giv

en t

he l

ack

of

dif

fere

nce

in

CV

D

even

ts a

nd

th

e i

ncr

ease

in

ad

ver

se

even

ts i

n t

he

agg

ress

ive

treat

men

t ar

m,

ther

e is

a p

oss

ibil

ity

th

at

ther

e m

ay n

ot

be f

avo

rab

le l

on

g-t

erm

ou

t-co

mes

.

It s

ho

uld

be

no

ted

th

at

this

stu

dy

fo

-

cuse

d o

n a

sin

gle

eth

nic

gro

up

.

[No

te:

Th

is s

tud

y d

id n

ot

con

tro

l fo

r

con

fou

nd

ing

by

ora

l h

ypo

gly

cem

ic

med

ica

tio

n u

se,

wh

ich

ma

y h

ave

b

iase

d r

esu

lts

aw

ay

fro

m t

he

nu

ll.]


www.icsi.org

90


Au

tho

r/Y

ear

Des

ign

T

yp

e C

lass

Q

ual

-it

y

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

ra

tio

, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

New

-m

an,

et

al.,

20

08

Th

e C

AR

DS

st

ud

y

RC

T

A

+

2,3

38

pat

ien

ts w

ith

ty

pe 2

dia

bete

s an

d

no

his

tory

of

coro

nar

y h

ear

t d

isea

se w

ho

w

ere

enro

lled

in

th

e C

oll

abo

rati

ve

Ato

rvas

tati

n D

iab

etes

Stu

dy

(C

AR

DS

) an

d f

oll

ow

ed f

or

3.9

yea

rs.

P

atie

nts

wer

e r

and

om

ized

to

rec

eiv

e at

orv

asta

tin

10

mg

/day

or

pla

ceb

o i

n a

d

ou

ble

-bli

nd

ed s

tud

y.

Th

e p

rim

ary

ou

tco

me

of

this

stu

dy

wa

s to

ev

alu

ate

th

e sa

fety

an

d t

ole

rab

ilit

y o

f a

torv

ast

ati

n 1

0 m

g/d

ay

w

ith

pla

ceb

o.

Th

e p

erce

nta

ge

of

pati

ents

ex

per

ien

cin

g a

dv

erse

ev

ents

, se

rio

us

adv

erse

ev

ents

, an

d d

isco

nti

nu

ati

on

s d

ue

to a

dv

erse

ev

ents

in

th

e ato

rvas

tati

n v

s. p

laceb

o

gro

up

s w

ere

23

.0%

vs.

25

.4%

, 1

.1%

vs.

1.1

%,

and

2

.9%

vs.

3.4

%,

resp

ecti

vel

y.

T

he

mo

st c

om

mo

n a

dv

erse

ev

ents

wer

e d

igest

ive

sys-

tem

rela

ted

.

Th

e au

tho

rs c

on

clu

de

that

ato

rvas

tati

n

10

mg

/day

was

well

to

lera

ted

in

pa-

tien

ts w

ith

ty

pe

2 d

iab

etes

du

rin

g r

ela

-

tiv

ely

lo

ng

-ter

m t

reatm

ent

(3.9

year

s)

and

th

at

pat

ien

ts w

ith

dia

bete

s b

enef

it

fro

m s

tati

n t

her

apy

.

[No

te:

Th

is s

tud

y w

as

un

ab

le t

o a

s-ce

rta

in l

on

g-t

erm

ou

tco

mes

of

trea

t-m

ent.

]

Mal

m-

stro

m,

et

al.,

20

09

(s

ame

stu

dy

as

Set

ter-

gre

n)

RC

T

A

Ø

32

pat

ien

ts w

ith

ty

pe 2

dia

bete

s o

r im

-p

aire

d g

luco

se t

ole

ran

ce

and

sta

ble

co

ron

ary

art

ery

dis

eas

e r

ece

ived

6

wee

ks

of

trea

tmen

t w

ith

sim

vast

atin

80

mg

/day

or

ezeti

mib

e 1

0 m

g/d

ay p

lus

sin

vas

tati

n 1

0 m

g/d

ay.

Th

e p

rim

ary

ou

tco

mes

of

this

stu

dy

were

LD

L c

ho

-le

ster

ol,

C-r

eact

ive p

rote

in, a

nd

pla

tele

t fu

nct

ion

.

To

tal

and

lo

w-d

ensi

ty L

DL

ch

ole

ster

ol

dec

reas

ed f

rom

3.2

(±

0.6

) to

1.7

(±

0.7

) in

th

e ez

itim

ibe +

sim

vas

tati

n

gro

up

an

d 3

.0 (

±1

.0)

to 1

.4 (

±0

.5)

in t

he

sim

vas

tati

n-

alo

ne g

rou

p.

Nei

ther

tre

atm

ent

affe

cte

d p

late

let

act

ivit

y (

pla

tele

t P

-se

lecti

n e

xp

ress

ion

an

d f

ibri

no

gen

bin

din

g,

AD

P-

ind

uce

d p

late

let

agg

reg

ati

on

).

Th

e au

tho

rs c

on

clu

de

that

pro

no

un

ced

li

pid

-lo

wer

ing

did

no

t in

flu

ence

in

di-

ces

of

pla

tele

t fu

nct

ion

. T

hes

e r

esu

lts

sug

ges

t th

at

nei

ther

th

e l

ipid

-lo

wer

ing

no

r th

e p

leio

tro

pic

eff

ects

of

stati

n

ther

apy

red

uce

d t

he r

eac

tiv

ity

of

pla

tele

t ag

gre

gat

ion

.

Th

is s

tud

y i

s li

mit

ed b

y a

sm

all

nu

m-

ber

of

pati

ents

. A

lso

, th

ere w

ere

som

e b

aseli

ne

dif

fere

nce

s in

clo

pi-

do

gre

l an

d a

spir

in u

se a

nd

gen

der

dis

-tr

ibu

tio

n.

Sev

er,

et

al.,

20

05

A

SC

OT

RC

T

A

+

2,5

32

pat

ien

ts w

ith

dia

bet

es a

t ra

nd

om

i-za

tio

n i

n t

he

AS

CO

T s

tud

y.

Pat

ien

ts

wer

e h

yp

erte

nsi

ve, w

ith

no

his

tory

of

coro

nar

y h

eart

dis

eas

e, b

ut

at

leas

t th

ree

card

iov

asc

ula

r ri

sk f

acto

rs.

R

and

om

ized

to

rece

ive

10

mg

ato

rvas

-ta

tin

or

pla

ceb

o.

Th

e p

rim

ary

ou

tco

me

of

this

stu

dy

wa

s a

co

mp

osi

te

of

tota

l ca

rdio

va

scu

lar o

utc

om

es.

Du

rin

g a

med

ian

fo

llo

w-u

p o

f 3

.3 y

ear

s, c

on

cen

trati

on

of

tota

l an

d L

DL

ch

ole

ster

ol

was

~1

mm

ol/

l lo

wer

in

th

ose

ran

do

miz

ed t

o a

torv

ast

atin

co

mp

ared

wit

h p

la-

ceb

o.

T

her

e w

ere 1

66

maj

or

card

iov

ascu

lar

even

ts (

9.2

%)

in

the

ato

rvast

atin

gro

up

an

d 1

51

(1

1.9

%)

in t

he

pla

ceb

o

gro

up

(H

azar

d r

atio

0.7

7,

95

% c

on

fid

ence

in

terv

al

0.6

1-0

.98

). T

her

e w

ere n

o s

tati

stic

ally

sig

nif

ican

t re

-d

uct

ion

s in

in

div

idu

al c

ard

iov

ascu

lar

end

po

ints

(s

tro

ke,

co

ron

ary

ev

ents

).

Th

e au

tho

rs c

on

clu

de

that

ato

rvas

tati

n

sig

nif

ican

tly

red

uced

th

e ri

sk o

f m

ajo

r ca

rdio

vasc

ula

r ev

ents

an

d p

roce

du

res

amo

ng

dia

beti

c p

ati

ents

wit

h w

ell

-

con

tro

lled

hy

per

ten

sio

n a

nd

wit

ho

ut

a h

isto

ry o

f co

ron

ary

hear

t d

isea

se.

Th

e re

du

ctio

n i

n r

isk

was

sim

ilar

to

th

at

amo

ng

stu

dy

par

ticip

ants

wh

o w

ere

no

t d

iag

no

sed

wit

h d

iab

etes

.

Th

is s

tud

y w

as l

imit

ed b

y r

ela

tiv

ely

sh

ort

fo

llo

w-u

p t

ime;

th

us,

th

e in

ves

-ti

gato

rs w

ere u

nab

le t

o a

ssess

lo

ng-

term

sta

tin

use

in

dia

beti

cs.

Th

is s

tud

y d

id n

ot

asse

ss m

icro

vas

cu-

lar

even

ts.


www.icsi.org

91


Au

tho

r/Y

ear

Des

ign

T

yp

e C

lass

Q

ual

-it

y

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

ra

tio

, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Kn

op

p,

et a

l.,

20

06

9

Th

e A

SP

EN

st

ud

y

RC

T

A

Ø

2,4

10

su

bje

cts

wer

e ra

nd

om

ly a

ssig

ned

to

rece

ive

10

mg

ato

rvast

atin

or

pla

ceb

o

in a

4-y

ear,

do

ub

le-b

lin

ded

stu

dy

.

Th

e p

rim

ary

en

d p

oin

t o

f th

is s

tud

y w

as

a c

om

pos-

ite

com

pro

mis

ed o

f ca

rd

iov

asc

ula

r d

eath

, n

on

-fa

tal

MI,

no

n-f

ata

l st

rok

e, r

eca

na

liza

tio

n,

coro

na

ry a

r-

tery

by

pa

ss s

urg

ery

, re

susi

cita

ted

ca

rdia

c a

rres

t,

an

d w

ors

enin

g o

r u

nst

ab

le a

ng

ina

. A

t th

e en

d o

f th

e 4-y

ear

stu

dy

, L

DL

ch

ole

ster

ol

was

red

uce

d b

y 3

0.1

% i

n t

he

ato

rvas

tati

n g

rou

p a

nd

1.1

%

in t

he

pla

ceb

o g

rou

p (

p=

0.0

00

1).

C

om

po

site

en

d p

oin

t ra

tes

wer

e 1

3.7

% i

n t

he

ato

rvas

-ta

tin

gro

up

an

d 1

5.0

% i

n t

he p

laceb

o g

rou

p (

Haz

ard

ra

tio

0.9

0, 9

5%

co

nfi

den

ce i

nte

rval

0.7

3-1

.12

).

Th

e au

tho

rs c

on

clu

de

that

th

ere w

ere

no

t si

gn

ific

ant

dif

fere

nces

bet

wee

n

gro

up

s in

co

mp

osi

te e

nd

po

ints

. T

hey

furt

her

ack

no

wle

dg

e th

at t

hes

e r

esu

lts

that

are

in

con

sist

ent

wit

h o

ther

s re

-p

ort

ed i

n t

he

lite

ratu

re m

ay b

e d

ue

to

the

pri

mar

y e

nd p

oin

t d

efin

itio

n

(wh

ich

may

hav

e b

een

in

flat

ed d

ue t

o

incl

usi

on

of

ho

spit

aliz

atio

n f

or

an-

gin

a) o

r p

roto

col

chan

ges

du

e t

o

chan

ges

in

tre

atm

ent

gu

idel

ines

.

Th

us,

beca

use

of

the i

ncr

eas

ed r

isk

of

coro

nar

y h

eart

dis

eas

e a

mo

ng

dia

bet

ic

pat

ien

ts,

they

sh

ou

ld s

till

be t

reate

d t

o

ach

iev

e L

DL

ch

ole

ster

ol

targ

ets

.

Tw

o y

ear

s in

to t

he s

tud

y,

the

stu

dy

p

roto

col

was

alt

ered

to

in

clu

de

pa-

tien

ts w

ith

ou

t p

rio

r M

I o

r in

terv

en-

tio

nal

pro

ced

ure

du

e t

o c

han

ges

in

tr

eatm

ent

gu

ideli

nes

.

Su

bse

qu

ent

trea

tmen

t g

uid

eli

nes

nec

essi

tate

d a

ll

seco

nd

ary

pre

ven

tio

n s

ub

jects

an

d

pri

mar

y p

rev

enti

on

su

bje

cts

wit

h a

p

rim

ary

CV

D e

nd

po

int

to d

isco

n-

tin

ue t

he

stu

dy

med

icati

on

(as

man

-

dat

ed b

y t

he

DS

MB

).


www.icsi.org

92


Au

tho

r/

Yea

r D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

ra

tio

, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Sh

eph

erd

, et

al.

, 2

00

6

Tre

ati

ng

to

N

ew T

ar-

get

s S

tud

y

(TN

T)

RC

T

A

+

1,5

01

pat

ien

ts w

ith

dia

bet

es a

nd

co

ro-

nar

y h

eart

dis

eas

e, w

ith

LD

L c

ho

lest

ero

l le

vels

<1

30

mg

/dL

wer

e r

and

om

ized

to

a eit

her

ato

rvas

tati

n 1

0 o

r 8

0 m

g/d

ay.

Pat

ien

ts w

ere f

oll

ow

ed f

or

a m

edia

n o

f 4

.9 y

ears

.

Th

e p

rim

ary

en

d p

oin

t o

f th

is s

tud

y w

as

tim

e to

firs

t ca

rdio

va

scu

lar e

ven

t (d

efin

ed a

s d

eath

fro

m

coro

na

ry h

eart

dis

ease

, n

on

-fa

tal

MI,

res

usc

ita

ted

card

iac

arr

est,

or

fata

l o

r n

on

-fa

tal

stro

ke)

.

Th

e m

ean

LD

L c

ho

lest

ero

l le

vel

s at

the e

nd

of

treat

-m

ent

wer

e 9

8.6

mg

/dl

wit

h 1

0 m

g a

torv

ast

atin

an

d

77

.0 m

g/d

l w

ith

80

mg

ato

rvas

tati

n.

A p

rim

ary

ev

ent

occ

urr

ed i

n 1

35

pat

ien

ts o

n 1

0 m

g

com

par

ed w

ith

10

3 p

ati

ents

on

80

mg

(H

aza

rd r

atio

0

.75

, 9

5%

co

nfi

den

ce i

nte

rval

0.5

8-0

.97

).

Th

ere w

ere s

ign

ific

ant

dif

fere

nce

s b

etw

een

gro

up

s in

fa

vo

r o

f ato

rvas

tati

n 8

0 m

g f

or

tim

e to

fir

st c

ere-

bro

vas

cula

r ev

ent

(0.6

9, 9

5%

co

nfi

den

ce

inte

rval

0.4

8-

0.9

8)

and

an

y c

ard

iov

ascu

lar

even

t (0

.85

, 9

5%

co

nfi

-

den

ce i

nte

rval

0.7

3-1

.00

).

Th

e au

tho

rs c

on

clu

de

that

am

on

g p

a-ti

ents

wit

h c

oro

nar

y h

eart

dis

eas

e an

d

dia

bete

s, i

nte

nsi

ve

stati

n t

her

apy

of

80

mg

ato

rvas

tati

n s

ign

fica

ntl

y r

edu

ced

th

e ra

te o

f m

ajo

r car

dio

vasc

ula

r ev

ents

by

25

co

mp

ared

to

10

mg

at

orv

asta

tin

.

Th

e w

ere n

o d

iffe

ren

ces

in r

ate

s o

f ad

ver

se e

ven

ts

betw

een

gro

up

s.

Th

is s

tud

y d

id n

ot

asse

ss m

icro

vas

cu-

lar

even

ts.

Th

is s

tud

y w

as n

ot

po

wer

ed t

o d

ete

ct

dif

fere

nces

in

mo

rtali

ty.

Th

is i

s a

po

st-h

oc

anal

ysi

s o

f a s

ub

po

pu

lati

on

fro

m t

he l

arg

er T

NT

stu

dy

.

[No

te:

In

tere

stin

gly

, th

ere w

as

no

d

iffe

ren

ce

in c

ard

iova

scu

lar

even

ts

bet

ween

pa

tien

ts w

ith

an

d w

ith

ou

t g

oo

d g

lycem

ic c

on

tro

l.]


www.icsi.org

93

Conclusion Grading Worksheet D – Annotations #13, 14, 27, 29 (Goals for Blood Pressure)


Work

Gro

up

's C

on

clu

sion

: F

or

pat

ien

ts w

ith

ty

pe

2 d

iab

etes

mel

litu

s, t

he

syst

oli

c b

loo

d p

ress

ure

go

al i

s le

ss t

han

130

mm

Hg

an

d

the

dia

sto

lic

blo

od

pre

ssu

re g

oal

is

less

th

an 8

0 m

mH

g.

Con

clu

sio

n G

rad

e: I

I

Au

tho

r/

Yea

r

Des

ign

Ty

pe

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e, c

on

-

fid

ence

inte

rval

, re

lati

ve

risk

, o

dd

s ra

tio

, li

keli

ho

od

rat

io,

nu

mb

er n

eed

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

-ci

zed

)

UK

Pro

-sp

ecti

ve

Dia

bete

s S

tud

y

Gro

up

(U

KP

DS

3

9),

19

98

RC

T

A

ø

-75

8 p

atie

nts

all

oca

ted

to

tig

ht

con

tro

l o

f B

P a

mo

ng

1,1

48

hy

per

ten

siv

e p

atie

nts

w

ith

ty

pe 2

dia

bete

s -4

00

pat

ien

ts t

reate

d w

ith

cap

top

ril

(25-5

0

mg

tw

ice

dai

ly),

35

8 w

ith

ate

no

lol

(50-1

00

m

g t

wic

e d

aily

) -A

ll p

atie

nts

ag

es

48

-60

yea

rs o

f ag

e (m

ean

ag

e o

f tr

eatm

ent

gro

up

s 5

6 y

ears

) -9

-yea

r fo

llo

w-u

p

-go

al o

f B

P <

15

0/8

5 m

m H

g

-Cap

top

ril

and

ate

no

lol

eual

lele

eff

ecti

ve i

n m

ean

BP

re-

du

ctio

n (

14

4/8

4 a

nd

14

3/8

1 m

m H

g, re

spec

tiv

ely

) -R

edu

cti

on

of

risk

of

mac

rov

ascu

lar

end

po

ints

wer

e si

mil

ar i

n t

he

two

gro

up

s (3

1%

an

d 3

7%

sh

ow

ed

det

erio

rati

on

in

reti

no

pat

hy

by

2 g

rad

es;

5%

an

d 9

%

dev

elo

ped

cli

nic

al g

rad

e a

lbu

min

uri

a g

reate

r th

an o

r eq

ual

to

30

0 m

g/l

) -S

imil

ar p

erce

nta

ge o

f p

ati

ents

req

uir

ed 3

or

mo

re a

nti

-h

yp

erte

nsi

ve

treat

men

ts (

27

% a

nd

31

%)

or

dev

elo

ped

h

yp

og

lyce

mic

att

ack

s b

ut

mean

wt

gain

was

gre

ater

in

th

e at

eno

lol

gro

up

(1

.6 k

g v

s 3

.4k

g)

-78

% c

apto

pri

l an

d 6

5%

ate

no

lol

pati

ents

tak

ing

tre

at-

men

t at

last

vis

it (

p<

0.0

00

1)

-Blo

od

pre

ssu

re l

ow

erin

g w

ith

ca

pto

pri

l o

r ate

no

lol

was

sim

i-la

rly

eff

ecti

ve i

n r

edu

cin

g t

he

in-

cid

ence

of

dia

beti

c co

mp

lica

-

tio

ns.

T

his

stu

dy

su

gg

ests

th

at

blo

od

pre

ssu

re r

edu

cti

on

in

its

elf

m

ay b

e m

ore

im

po

rtan

t th

an t

he

trea

tmen

t u

sed

.

UK

Pro

-sp

ecti

ve

Dia

bete

s S

tud

y

Gro

up

(U

KP

DS

3

8),

19

98

RC

T

A

+

-1,1

48

hy

per

ten

siv

e p

atie

nts

wit

h t

yp

e 2

d

iab

ete

s

-75

8 p

atie

nts

all

oca

ted

to

tig

ht

con

tro

l o

f B

P w

ith

go

al

of

<1

50

/85

mm

Hg

(4

00

pa-

tien

ts t

reate

d w

ith

cap

top

ril

[25-5

0 m

g

twic

e d

ail

y],

35

8 w

ith

ate

no

lol

[50-1

00

mg

tw

ice d

ail

y])

an

d 3

90

pat

ien

ts a

llo

cate

d t

o

less

tig

ht

con

tro

l o

f B

P w

ith

go

al

of

<1

80

/10

5 m

m H

g

-All

pat

ien

ts a

ges

48

-60

yea

rs o

f ag

e (m

ean

ag

e o

f tr

eatm

ent

gro

up

s 5

6 y

ears

) -8

.4-y

ear

foll

ow

-up

-Mean

BP

was

sig

nif

ican

tly

red

uce

d i

n t

he t

igh

t B

P

gro

up

(1

44

/82

Hg

mm

) as

co

mp

ared

to

th

e le

ss-t

igh

t B

P

gro

up

(an

d 1

54

/87

mm

Hg

, p

<0

.00

01

) -R

edu

cti

on

s o

f ri

sk i

n t

he t

igh

t B

P g

rou

p a

s co

mp

ared

to

th

e le

ss t

igh

t B

P g

rou

p w

ere

24

% i

n d

iab

ete

s-re

late

d e

nd

p

oin

ts (

95

CI

8%

to

38

%,

p=

0.0

04

6),

32

% i

n d

eat

hs

re-

late

d t

o d

iab

ete

s (9

5C

I 6

% t

o 5

1%

, p

=0

.01

9),

44

% i

n

stro

kes

(9

5C

I 1

1%

to

65

%,

p=

0.0

13

), 3

7%

in

mic

rov

as-

cula

r en

d p

oin

ts (

95

CI

11

% t

o 5

6%

, p

=0

.00

92

)

-Tig

ht

BP

gro

up

had

a 3

4%

red

ucti

on

in

ris

k o

f p

rop

or-

tio

n w

ith

dete

rio

rati

on

in

reti

no

path

y b

y 2

gra

des

(9

9C

I 1

1%

to

50

%,

p=

0.0

00

4),

an

d a

47

% r

edu

ced

ris

k f

or

de-

teri

ora

tio

n i

n v

isu

al a

cuit

y (

99

CI

7%

to

70

%, p

=0

.00

4)

-Tig

ht

blo

od

pre

ssu

re c

on

tro

l in

p

atie

nts

wit

h h

yp

erte

nsi

on

an

d

typ

e 2

dia

bet

es a

chie

ved

a c

lin

i-ca

lly

im

po

rtan

t re

du

cti

on

in

th

e

risk

of

deat

hs

rela

ted

to

dia

bet

es,

com

pli

cat

ion

s re

late

d t

o d

iab

etes

, p

rog

ress

ion

of

dia

beti

c re

tin

op

a-th

y,

and

dete

rio

rati

on

in

vis

ual

ac

uit

y.

Han

sso

n e

t al

., 1

99

8

Hy

per

ten

-si

on

Op

ti-

mal

Tre

at-

men

t

(HO

T)

Tri

al

RC

T

A

ø

-1,5

10

pat

ien

ts w

ith

dia

bet

es (

amo

ng

1

8,7

90

to

tal

pat

ien

ts w

ith

hy

per

ten

sio

n

and

dia

sto

lic

BP

10

0-1

15

mm

HG

in

tri

al)

-All

pat

ien

ts a

ges

50

-80

yea

rs o

f ag

e

-Pat

ien

ts r

and

om

ly a

ssig

ned

a t

arg

et

dia

-st

oli

c B

P o

f le

ss t

han

or

equ

al

to 9

0 m

m

Hg

, 8

5 m

m H

g,

or

80

mm

Hg

-All

pat

ien

ts r

ecei

ved

felo

dip

ine

for

hy

per

-te

nsi

on

-A

CE

in

hib

ito

rs o

r B

-blo

cker

s w

ere

use

d

to t

reat

to g

iven

tar

get

dia

sto

lic B

P

-3-

to 8

-yea

r fo

llo

w-u

p

-Fo

r p

atie

nts

wit

h d

iab

etes

, th

e b

loo

d p

ress

ure

in

terv

en-

tio

n l

ed t

o a

sig

nif

ican

t re

du

cti

on

(5

1%

) in

nu

mb

er o

f m

ajo

r car

dio

vas

cula

r ev

ents

(4

5 e

ven

ts i

n 9

0 m

m H

G

gro

up

, 3

4 i

n 8

5 m

m H

G g

rou

p, an

d 2

2 i

n 8

0 m

m H

G

gro

up

; p

=0

.00

5 f

or

tren

d)

and

car

dio

vas

cula

r m

ort

alit

ies

(21

, 2

1 a

nd

7;

p=

0.0

16

) -F

or

pat

ien

ts w

ith

dia

bet

es,

the

blo

od

pre

ssu

re i

nte

rven

-

tio

n r

edu

ced

to

tal

mo

rtal

ity

(3

0, 2

9, 1

7 e

ven

ts),

MIs

(1

4,

8, 7

) an

d s

tro

ke (

17

, 1

3, 1

2),

bu

t n

on

e w

as

stati

stic

ally

si

gn

ific

ant

-In

ten

siv

e lo

wer

ing

of

BP

in

dia

-b

etes

pati

ents

wit

h h

yp

erte

nsi

on

w

as a

sso

cia

ted

wit

h a

sig

nif

i-ca

ntl

y 5

1%

lo

wer

rat

e o

f ca

rdio

-v

ascu

lar

even

ts.

Upd

ated

Thi

rteen

th E

ditio

n, M

ay 2

009.


www.icsi.org

94

Conclusion Grading Worksheet E – Annotations #13, 14 (Aspirin Use)


Upd

ated

Thi

rteen

th E

ditio

n, M

ay 2

009.

Wo

rk G

rou

p's

Co

ncl

usi

on

:

Th

ere

is i

nsu

ffic

ien

t ev

iden

ce t

o s

up

po

rt a

spir

in u

se i

n t

he

pri

mar

y p

rev

enti

on

of

card

iov

ascu

lar

even

ts i

n p

atie

nts

wit

h t

yp

e 2

dia

bet

es,

alth

ou

gh

th

ere

is n

o e

vid

ence

of

sig

nif

ican

t h

arm

. H

ow

ever

, th

ere

is s

uff

icie

nt

evid

ence

to

su

pp

ort

th

e u

se o

f as

pir

in

for

seco

nd

ary

pre

ven

tio

n o

f ca

rdio

vas

cula

r ev

ents

in

pat

ien

ts w

ith

ty

pe

2 d

iab

etes

.

Co

nclu

sio

n G

ra

de:

I

Au

tho

r/Y

ear

D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p

-val

ue,

co

nfi

den

ce

inte

rval

, re

lati

ve

risk

, o

dd

s ra

tio

, li

kel

iho

od

rati

o,

nu

mb

er n

eed

ed

to t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Ear

ly T

reat-

men

t D

ia-

bet

ic R

eti-

no

pat

hy

S

tud

y

(ET

DR

S)

Rep

ort

14

, 1

99

2

RC

T

A

ø

-3,7

11

pat

ien

ts w

ith

dia

bet

es m

ell

itu

s (3

1%

ty

pe 1

, 3

1%

ty

pe

2,

and

39

% t

yp

e 1

o

r 2

) ra

nd

om

ized

to

rece

ive a

spir

in o

r p

la-

ceb

o (

65

0 m

g t

wic

e d

ail

y)

-All

pat

ien

ts a

ges

18-7

0 y

ears

of

age

-5-y

ear

foll

ow

-up

-RR

fo

r to

tal

mo

rtal

ity

was

0.9

1 (

99C

I 0

.75

-1

.11

, p

=N

S)

ov

erall

an

d 0

.92

in

ty

pe 2

p

atie

nts

(9

9C

I 0

.69

-1.2

3, p

=N

S)

trea

ted

vs.

p

laceb

o p

ati

ents

-M

yo

car

dia

l in

farc

tio

n r

ate

s w

ere

9.1

% w

ith

as

pir

in a

nd

12

.3%

wit

h p

laceb

o (

RR

0.8

3,

p=

0.0

4)

ov

erall

-T

he

NN

T t

o p

rev

ent

on

e M

I in

5 y

ears

wit

h

asp

irin

was

31

pati

ents

-Asp

irin

use

may

red

uce

th

e ri

sk o

f m

yo

-ca

rdia

l in

farc

tio

n i

n a

du

lts

wit

h d

iab

etes

bu

t d

id n

ot

red

uce

to

tal

mo

rtali

ty o

r C

V m

ort

al-

ity

rat

es.

-Th

ere

was

no

ev

iden

ce

of

har

mfu

l ef

fect

s o

f as

pir

in.

-Th

e E

TD

RS

res

ult

s su

pp

ort

use

of

asp

irin

in

per

son

s w

ith

dia

bete

s at

incr

ease

d r

isk

of

card

iov

asc

ula

r d

iseas

e.

Han

sso

n e

t al

., 1

99

8

Hy

per

ten

sio

n

Op

tim

al

Tre

atm

ent

(HO

T)

Tri

al

RC

T

A

ø

-1,5

10

pat

ien

ts w

ith

dia

bet

es (

amo

ng

1

8,7

90

to

tal

pat

ien

ts w

ith

hy

per

ten

sio

n

and

dia

sto

lic

BP

10

0-1

15

mm

HG

in

tri

al)

-All

pat

ien

ts a

ges

50-8

0 y

ears

of

age

-P

atie

nts

ran

do

mly

ass

ign

ed a

tar

get

dia

-st

oli

c B

P o

f le

ss t

han

or

equ

al

to 9

0 m

m

Hg

, 8

5 m

m H

g,

or

80

mm

Hg

-All

stu

dy

su

bje

cts

wer

e ra

nd

om

ized

to

re

ceiv

e a

spir

in 7

5 m

g/d

ay o

r p

laceb

o

-3 t

o 8

-yea

r fo

llo

w-u

p

-Fo

r al

l p

atie

nts

, as

pir

in u

se s

ign

ific

antl

y r

e-d

uce

d c

ard

iov

asc

ula

r ev

ents

15

% (

p=

0.0

3)

and

red

uced

MI

rate

s 3

6%

(p

=0

.00

2)

bu

t d

id

no

t re

du

ce

mo

rtali

ty

-Th

e re

lati

ve

ben

efit

of

asp

irin

to

th

ose

wit

h

dia

bete

s w

as

“ab

ou

t th

e s

ame”

as

in t

he

wh

ole

tri

al p

op

ula

tio

n

-Use

of

asp

irin

in

dia

bete

s an

d i

n n

on-

dia

bete

s p

ati

ents

sig

nif

ican

tly

red

uced

MIs

(3

6%

) an

d c

ard

iov

ascu

lar

even

ts (

15

%)

bu

t d

id n

ot

sig

nif

ican

tly

red

uce

mo

rtal

ity

. -A

spir

in u

se (

75

mg

/day

) ap

pear

s to

ben

efit

d

iab

ete

s p

ati

ents

wit

h h

yp

erte

nsi

on

, ev

en

tho

se i

n w

ho

m b

loo

d p

ress

ure

is

ver

y w

ell

con

tro

lled

.

Har

paz

, et

al.,

19

98

Co

ho

rt

B

+

-2,3

68

NID

DM

ad

ult

s w

ith

CH

D a

nd

8,5

86

no

n-N

IDD

M a

du

lts

wit

h C

HD

-M

ean

fo

llo

w-u

p 5

.1 y

ears

-5

2%

of

NID

DM

pat

ien

ts r

epo

rted

no

A

SA

use

-All

-cau

se m

ort

ali

ty w

as 1

8.4

% i

n N

IDD

M

AS

A u

sers

an

d 2

6.2

% i

n N

IDD

M A

SA

no

n-

use

rs (

p <

0.0

01

) -C

ard

iac m

ort

ali

ty w

as 1

0.9

% i

n

NID

DM

A

SA

use

rs a

nd

15

.9%

in

NID

DM

AS

A n

on-

use

rs (

p <

0.0

01

) -B

oth

sig

nif

ican

t d

iffe

ren

ces

per

sist

ed a

fter

ad

just

men

t fo

r p

oss

ible

co

nfo

un

der

s

-Tre

atm

ent

wit

h A

SA

was

ass

ocia

ted

wit

h a

sig

nif

ican

t re

du

ctio

n i

n c

ard

iac a

nd

to

tal

mo

rtali

ty a

mo

ng

NID

DM

ad

ult

s w

ith

CH

D.

-Th

e ab

solu

te b

enef

it o

f as

pir

in w

as g

reate

r in

dia

bete

s v

ersu

s n

on-d

iab

ete

s ad

ult

s.

Ph

ysi

cia

n’s

Hea

lth

Stu

dy

R

esea

rch

G

rou

p, 1

98

9

RC

T

A

ø

-Pri

mar

y p

rev

enti

on

of

MI

in s

ub

gro

up

of

53

3 p

hy

sici

ans

wit

h d

iab

etes

(am

on

g

22

,07

1 t

ota

l p

arti

cip

ants

) -P

atie

nts

ran

do

miz

ed t

o e

ith

er 3

25

mg

A

SA

/day

or

pla

ceb

o

-Mean

fo

llo

w-u

p 5

year

s

-Ov

eral

l, 4

4%

red

uct

ion

in

MI

(p<

0.0

00

01

)

in t

ho

se w

ho

to

ok

AS

A

-In

dia

bete

s su

bg

rou

p, 4

.0%

had

MI

in A

SA

g

rou

p (

11

/27

5)

and

10

.1%

had

MI

in n

on-

AS

A g

rou

p (

p=

0.2

2, N

S)

-Rela

tiv

e ri

sk o

f M

I in

AS

A g

rou

p w

as 0

.60

in

en

tire

co

ho

rt,

and

0.3

9 i

n d

iab

ete

s

-Asp

irin

red

uce

d M

I ra

te i

n o

ver

all

stu

dy

.

-Ben

efit

s in

DM

gro

up

ap

pea

r to

be

at l

east

as

gre

at a

s in

no

n-D

M g

rou

p.

-Th

e n

on

-sig

nif

ica

nt

dif

fere

nce

s in

DM

g

rou

p w

ere

like

ly d

ue t

o s

ma

ll s

am

ple

siz

e a

nd

in

suff

icie

nt

po

wer.


www.icsi.org

95

Conclusion Grading Worksheet E – Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Annotations #13, 14 (Aspirin Use) Thirteenth Edition/May 2009

Au

tho

r/Y

ear

Des

ign

T

yp

e C

lass

Q

ual

-it

y

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p

-val

ue,

co

nfi

den

ce

inte

rval

, re

lati

ve

risk

, o

dd

s ra

tio

, li

kel

iho

od

rati

o,

nu

mb

er n

eed

ed

to t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Og

awa,

et a

l.,

20

08

RC

T

A

+

2,5

39

pat

ien

ts w

ith

ty

pe 2

dia

bete

s fr

ee

of

ath

ero

scle

roti

c d

isea

se r

ecru

ited

fro

m 1

63

in

-

stit

uti

on

s th

rou

gh

ou

t Ja

pan

. P

ati

ents

wer

e

ran

do

miz

ed t

o 8

1 o

r 1

00

mg

asp

irin

per

day

or

no

n-a

spir

in g

rou

p (

JPA

D s

tud

y).

Tri

al

was

con

du

cted

fro

m 2

00

2-2

00

6.

Med

ian

fo

llo

w-u

p t

ime

was

4.3

7 y

ears

.

Th

e p

rim

ary

ou

tco

me

was

ath

ero

scle

roti

c

even

ts,

inclu

din

g f

ata

l an

d n

on

-fat

al

isch

emic

hea

rt d

iseas

e, fa

tal

and

no

n-f

ata

l

stro

ke,

an

d p

erip

her

al

arte

rial

dis

ease

.

Haz

ard

rati

os:

(9

5%

co

nfi

den

ce

inte

rval

s)

All

ath

ero

scle

roti

c ev

ents

: 0

.80

(0

.58

-1.1

0)

Co

ron

ary

an

d c

ereb

rov

ascu

lar

mo

rtal

ity

:

0.1

0 (

0.0

1-0

.79

)

CH

D e

ven

ts (

fata

l an

d n

on-f

atal)

: 0

.81

(0

.49

-

1.3

3)

No

n-f

atal

MI:

1.3

4 (

0.5

7-3

.19

)

Un

stab

le a

ng

ina:

0.4

0 (

0.1

3-1

.29

)

Sta

ble

an

gin

a: 1

.10

(0

.49-2

.50

)

Cer

ebro

vas

cula

r d

iseas

e (f

ata

l an

d n

on-

fata

l):

0.8

4 (

0.5

3-1

.32

)

Fat

al s

tro

ke:

0.2

0 (

0.2

4-1

.74

)

No

n-f

atal

stro

ke

isch

emic

: 0

.93

(0

.52-1

.66

)

No

n-f

atal

stro

ke

hem

orr

hag

ic:

1.6

8 (

0.4

0-

7.0

4)

Tra

nsi

ent

isch

em

ic a

ttack

: 0

.63

(0

.21-1

.93

)

PA

D:

0.6

4 (

0.2

5-1

.65

)

Th

e au

tho

rs c

on

clu

de

that

low

-do

se a

spir

in

use

do

es n

ot

red

uce

car

dio

vas

cula

r ev

ents

in p

ati

ents

wit

h t

yp

e 2

dia

bet

es.

Th

is s

tud

y f

aced

tw

o i

mp

ort

ant

lim

itati

on

s:

1)

th

e s

tud

y d

esig

n w

as

no

t b

lin

ded

be-

cau

se l

aw i

n J

apan

do

es n

ot

allo

w d

octo

rs

to d

isp

ense

pla

ceb

o;

and

2)

the

ath

ero

scle

-

roti

c e

ven

t ra

te w

as l

ow

er t

han

an

tici

pat

ed

and

as

a r

esu

lt,

the

JPA

D t

rial

was

no

t

po

wer

ed t

o d

emo

nst

rate

th

at a

spir

in h

ad a

sig

nif

ican

t ef

fect

on

red

ucin

g t

ota

l at

her

o-

scle

roti

c e

ven

ts.

Ho

wev

er,

the

auth

ors

ad

e-

qu

ately

ack

no

wle

dg

e th

ese

lim

itati

on

s.

Ad

dit

ion

ally

, th

ey i

nd

icate

th

at t

he

resu

lts

sho

uld

be

tak

en i

nto

th

e co

nte

xt

of

low

ath

ero

scle

roti

c d

isea

se r

ates

in

Jap

an.


www.icsi.org

96

Au

tho

r/Y

ear

Des

ign

T

yp

e C

lass

Q

ual

-it

y

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p

-val

ue,

co

nfi

den

ce

inte

rval

, re

lati

ve

risk

, o

dd

s ra

tio

, li

kel

iho

od

rati

o,

nu

mb

er n

eed

ed

to t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Belc

h, et

al.,

20

08

RC

T

A

+

1,2

76

ad

ult

s ag

ed 4

0 o

r m

ore

yea

rs w

ith

ty

pe

1 o

r ty

pe 2

dia

bete

s an

d a

nk

le b

rach

ial

pre

s-

sure

in

dex

of

0.9

9 o

r le

ss b

ut

no

sy

mp

tom

atic

CV

D.

Pat

ien

ts w

ere r

and

om

ized

to

10

0 m

g

asp

irin

per

day

plu

s an

tio

xid

ant

cap

sule

(n=

32

0),

pla

ceb

o t

able

t p

lus

anti

ox

idan

ts c

ap-

sule

(n

=3

20

), o

r p

laceb

o t

able

t p

lus

pla

ceb

o

cap

sule

(n

=3

18

).

Th

e m

edia

n l

eng

th o

f fo

llo

w-u

p w

as

6.7

yea

rs

and

fo

r th

ose

wit

h a

fin

al

foll

ow

-up

in

20

06

,

foll

ow

-up

ran

ged

fro

m 4

.5 t

o 8

.6 y

ear

s, r

e-

sult

ing

in

a t

ota

l 8

.12

7 p

erso

n-y

ears

of

ob

serv

atio

n.

Th

ere w

ere

two

pri

mar

y o

utc

om

e m

easu

res:

1)

a co

mp

osi

te o

f d

eat

h f

rom

CH

D o

r st

rok

e,

no

n-f

atal

MI

or

stro

ke, o

r am

pu

tati

on

ab

ov

e

the

ank

le f

or

crit

ical

lim

b i

sch

em

ia;

or

2)

dea

th f

rom

CH

D o

r st

rok

e. S

eco

nd

ary

end

-

po

ints

in

clu

ded

death

fro

m a

ny

cau

se;

dea

th

fro

m s

tro

ke, n

on

-fat

al

MI

or

stro

ke, o

r am

pu

-

tati

on

ab

ov

e th

e an

kle

fo

r cr

itic

al

lim

b

isch

emia

; d

evel

op

men

t o

f an

gin

a; C

AB

G;

ang

iop

last

y;

PA

D b

yp

ass

surg

ery

; P

AD

an

-

gio

pla

sty

.

Haz

ard

rati

os

(95

% c

on

fid

ence

in

terv

als

) fo

r

asp

irin

vs.

no

n-a

spir

in

Co

mp

osi

te e

nd

po

int:

0.9

8 (

0.7

6-1

.26

)

Dea

th f

rom

CH

D o

r st

rok

e: 1

.23

(0

.79-1

.93

)

Dea

th a

ny

cau

se:

0.9

3 (

0.7

1-1

.24

)

CH

D d

eath

: 0

.93

(0

.81-2

.25

)

Str

ok

e d

eath

: 0

.89

(0

.34-2

.30

)

No

n-f

atal

MI:

0.9

8 (

0.6

8-1

.43

)

No

n-f

atal

stro

ke:

0.7

1 (

0.4

4-1

.14

)

Ab

ov

e-an

kle

am

pu

tati

on

: 1

.23

(0

.51-2

.97

)

Tra

nsi

ent

isch

em

ic a

ttack

: 0

.70

(0

.36-1

.39

)

Th

e au

tho

rs f

ou

nd

no

ev

iden

ce t

o s

up

po

rt

the

use

of

asp

irin

in

th

e p

rim

ary

pre

ven

tio

n

of

card

iov

ascu

lar

even

ts o

r m

ort

alit

y i

n

peo

ple

wit

h d

iab

ete

s.

Th

e a

uth

ors

no

te t

hat

asp

irin

sh

ou

ld b

e u

sed

fo

r se

con

dar

y p

re-

ven

tio

n o

f ca

rdio

vas

cula

r ev

ents

.

Th

is s

tud

y w

as o

rig

inall

y d

esig

ned

to

re-

cru

it 1

,60

0 p

ati

ents

wit

h f

oll

ow

-up

of

fou

r

yea

rs,

wit

h o

ne e

ffec

tiv

e tr

eatm

ent

that

wo

uld

hav

e p

rov

ided

po

wer

of

90

% t

o d

e-

tect

a 2

5%

rel

ativ

e r

isk

red

ucti

on

in

a f

ou

r-

yea

r ev

ent

rate

of

28

% (

8%

per

an

nu

m a

t

the

0.0

5 l

evel)

– e

qu

atin

g t

o 3

92

ev

ents

.

Wit

h b

oth

tre

atm

ents

eq

ual

ly e

ffec

tiv

e, t

hat

wo

uld

hav

e p

rov

ided

80

% p

ow

er t

o d

etec

t

for

each

tre

atm

ent

rate

th

e s

am

e r

ela

tiv

e re

-

du

ctio

n i

n e

ven

t ra

te a

s si

gn

ific

ant, r

esu

lt-

ing

in

34

3 e

ven

ts.

Ho

wev

er,

du

e to

slo

wer

than

an

ticip

ate

d r

ecru

itm

ent

and

lo

wer

even

t ra

tes,

on

ly 1

,27

6 p

ati

ents

wer

e re

-

cru

ited

, w

ith

25

6 e

ven

ts r

esu

ltin

g p

ow

er b

e-

ing

red

uced

to

73

% t

o d

etec

t a

25

% r

ela

tiv

e

red

uct

ion

in

ev

ent

rate

an

d 8

9%

po

wer

to

det

ect

a 3

0%

red

ucti

on

in

ev

ent

rate

if

on

ly

on

e tr

eatm

ent

was

eff

ect

ive.

Wal

sh

and

Sp

url

ing

,

20

08

Nar

rati

ve

rev

iew

R

- N

arra

tiv

e r

evie

w o

f ev

iden

ce

to s

up

po

rt p

ro-

ph

yla

cti

c u

se o

f as

pir

in i

n t

yp

e 2

dia

bete

s.

Su

mm

ariz

ed f

ind

ing

s fr

om

a s

yst

emat

ic r

e-

vie

w t

hat

on

ly e

xam

ined

dia

bete

s as

a s

ub

set

of

the

stu

dy

; als

o,

they

rev

iew

ed 3

ran

dom

-

ized

co

ntr

oll

ed t

rial

s.

Th

e s

yst

em

ati

c re

vie

w

and

2 o

f th

e R

CT

s d

id n

ot

sup

po

rt t

he

use

of

asp

irin

in

peo

ple

wit

h d

iab

etes

fo

r p

rev

en-

tio

n o

f M

I o

r m

ort

ali

ty.

On

ly o

ne

(sm

all

)

RC

T s

up

po

rted

th

e u

se o

f as

pir

in.

Th

e au

tho

rs c

on

clu

de

that

mo

st a

vail

able

evid

ence

do

no

t su

pp

ort

gu

ideli

nes

fro

m t

he

Am

eric

an D

iab

ete

s A

sso

ciat

ion

an

d t

he

Au

stra

lian

Nat

ion

al H

eal

th a

nd

Med

ical

Res

earc

h C

ou

nci

l.



www.icsi.org

97

Au

tho

r/Y

ear

Des

ign

T

yp

e C

lass

Q

ual

-it

y

+,–

,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p

-val

ue,

co

nfi

den

ce

inte

rval

, re

lati

ve

risk

, o

dd

s ra

tio

, li

kel

iho

od

rati

o,

nu

mb

er n

eed

ed

to t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Gae

de,

et

al.

, 2

00

8

Th

e S

ten

o-2

S

tud

y

RC

T

A

- 1

60

pat

ien

ts w

ith

ty

pe

2 d

iab

etes

an

d p

ersi

s-te

nt

mic

roal

bu

nar

ia w

ere

ran

do

miz

ed t

o r

e-ce

ive

eith

er i

nte

nsi

ve

ther

apy

or

con

ven

tio

nal

th

erap

y.

Th

e m

ean

tre

atm

ent

per

iod

was

7.8

y

ears

.

Th

e p

rim

ary

en

d p

oin

t w

as d

eath

fro

m a

ny

ca

use

. 2

4 p

atie

nts

die

d i

n t

he

inte

nsi

ve

ther

-ap

y g

rou

p c

om

par

ed w

ith

40

in

th

e co

nv

en-

tio

n t

her

apy

gro

up

, (H

azar

d r

atio

0.5

4, [9

5%

co

nfi

den

ce i

nte

rval

0.3

2-0

.89

]).

In

ten

siv

e th

erap

y w

as a

sso

ciat

ed w

ith

a

low

er r

isk

of

dea

th f

rom

car

dio

vas

cula

r ca

use

s, (

Haz

ard

rat

io 0

.43

(9

5%

CI

0.1

9-

0.9

4)

and

lo

wer

ris

k o

f ca

rdio

vas

cula

r ev

ents

(H

azar

d r

atio

0.4

1 [

95

% C

I 0

.25

-0.6

7])

. A

spir

in u

se f

or

the

inte

nsi

ve

vs.

con

ven

tio

nal

g

rou

p, re

spec

tiv

ely

, w

ere

14

% a

nd

13

% a

t b

asel

ine,

87

% a

nd

56

% a

t en

d o

f in

terv

en-

tio

n,

and

85

% a

nd

76

% a

t en

d o

f fo

llo

w-u

p.

At

the

end

of

foll

ow

-up

, th

ere

was

no

t a

sta-

tist

ical

dif

fere

nce

in

asp

irin

use

bet

wee

n

gro

up

s.

Th

e au

tho

rs c

on

clu

de

that

in

at-

risk

pat

ien

ts

wit

h t

yp

e 2

dia

bet

es,

inte

nsi

ve

inte

rven

tio

n

wit

h m

ult

iple

dru

g c

om

bin

atio

ns

and

be-

hav

ior

mo

dif

icat

ion

had

su

stai

ned

ben

efi-

cial

eff

ects

wit

h r

esp

ect

to v

ascu

lar

com

pli

-ca

tio

ns

and

on

rat

es o

f d

eath

fro

m a

ny

ca

use

an

d f

rom

car

dio

vas

cula

r ca

use

s.

Th

is s

tud

y w

as n

ot

des

ign

ed t

o i

den

tify

w

hic

h e

lem

ents

of

inte

nsi

ve

dia

bet

es t

her

-ap

y c

on

trib

ute

d m

ost

to

red

uct

ion

in

car

-d

iov

ascu

lar

risk

.

[Wit

h r

ega

rd t

o a

spir

in,

ther

e i

s n

o e

vi-

den

ce i

n t

his

pa

per

th

at

dir

ectl

y su

pp

ort

s

the

use

of

asp

irin

fo

r p

rim

ary

pre

ven

tio

n i

n

pa

tien

ts w

ith

dia

bete

s.

Ba

sed

on

th

e fi

nd

-

ing

s p

rese

nte

d,

it i

s im

po

ssib

le t

o d

ete

rmin

e

wh

at,

if

an

y, o

f th

e b

enefi

t is

att

rib

uta

ble

to

asp

irin

. I

t is

fu

rth

er c

om

pli

cate

d b

y fa

ct

tha

t a

t th

e en

d o

f th

e fo

llo

w-u

p p

eri

od

,

ther

e w

as

no

dif

fere

nce

in a

spir

in u

se b

e-

twee

n g

rou

ps.

]

Sir

ois

, et

al.,

20

08

Sy

stem

-

atic

re-

vie

w

M

Ø

Med

lin

e an

d E

mb

ase

dat

abas

es w

ere

sear

ched

for

stu

die

s ev

alu

atin

g t

he

effe

ct o

f as

pir

in o

n

card

iov

ascu

lar

ou

tco

mes

in

pat

ien

ts w

ith

ty

pe

2 d

iab

etes

.

Fo

ur

stu

die

s m

et t

he

incl

usi

on

cri

teri

a –

th

ree

RC

Ts

and

on

e o

bse

rvat

ion

al s

tud

y.

Th

e th

ree

RC

Ts

did

no

t p

rov

ide

evid

ence

to

sup

-p

ort

asp

irin

th

erap

y i

n t

yp

e 2

dia

bet

es.

Re-

du

ctio

n i

n c

ard

iac

mo

rtal

ity

was

fo

un

d i

n t

he

ob

serv

atio

nal

stu

dy

.

Th

ese

fin

din

gs

sug

ges

t th

at t

he

clin

ical

gu

idel

ines

may

be

bas

ed o

n e

xp

ecte

d b

ene-

fit

corr

elat

ed t

o w

hat

has

bee

n o

bse

rved

in

o

ther

hig

h-r

isk

po

pu

lati

on

s.

G

iven

th

e la

ck o

f h

ard

ev

iden

ce a

nd

th

e d

if-

fere

nce

in

pla

tele

t p

hy

sio

log

y i

n d

iab

etes

p

atie

nts

, as

pir

in u

se a

s a

stan

dar

d t

reat

men

t sh

ou

ld b

e re

vis

ited

.



www.icsi.org

98

Au

tho

r/

Yea

r D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p

-val

ue,

co

nfi

den

ce

inte

rval

, re

lati

ve

risk

, o

dd

s ra

tio

, li

kel

iho

od

rati

o,

nu

mb

er n

eed

ed

to t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Ev

ang

elis

ta,

et a

l.,

20

07

C

ase

con

tro

l st

ud

y

C

Ø

Cas

es w

ere

82

pat

ien

ts w

ho

wer

e ta

kin

g a

s-p

irin

10

0 m

g/d

ay f

or

at l

east

on

e m

on

th w

ith

an

d w

ith

ou

t p

rio

r C

VD

ev

ents

. C

on

tro

ls p

a-ti

ents

wer

e id

enti

fied

am

on

g t

ho

se a

tten

din

g

card

iolo

gy

ou

tpat

ien

t u

nit

fo

r a

rou

tin

e v

isit

. C

on

tro

l p

atie

nts

did

no

t h

ave

dia

bet

es.

Con

-se

cuti

ve

pat

ien

ts w

ere

enro

lled

wit

h a

mat

ch

of

2:1

(ca

ses:

con

tro

ls).

Th

e o

bje

ctiv

e o

f th

is s

tud

y w

as t

o e

xp

lore

th

e h

yp

oth

esis

th

at a

spir

in i

s le

ss l

ikel

y t

o

adeq

uat

ely

su

pp

ress

bio

chem

ical

mar

ker

s o

f in

flam

mat

ion

an

d p

late

let

acti

vat

ion

in

pa-

tien

ts w

ith

dia

bet

es c

om

par

ed t

o t

ho

se w

ith

-o

ut

dia

bet

es.

Th

e re

sult

s sh

ow

ed t

hat

Tx

A2

(p

har

mac

ol-

og

ical

tar

get

of

asp

irin

) sy

nth

esis

an

d c

ircu

-la

tio

n l

evel

s o

f m

ark

ers

of

pla

tele

t ac

tivat

ion

sC

D4

0L

an

d s

P-s

elec

tio

n)

in p

atie

nts

wit

h

and

wit

ho

ut

dia

bet

es w

ho

wer

e tr

eate

d w

ith

lo

w-d

ose

asp

irin

. T

he

od

ds

of

hav

ing

11-

deh

yd

ro-T

xB

2 w

ith

in t

he

up

per

qu

arti

le w

as

3.9

(9

5%

CI

1.1

-14

.3)

in p

atie

nts

wit

h d

iabe-

tes

com

par

ed t

o c

on

tro

ls.

Th

e o

dd

s o

f h

av-

ing

sC

D4

0L

an

d s

P-s

elec

tio

n w

ith

in t

he

up

-p

er q

uar

tile

was

12

.6 (

95

% C

I 2

.4-6

5.5

) h

igh

er i

n c

ases

th

an c

on

tro

ls.

Th

ere

wer

e n

ot

sub

stan

tial

dif

fere

nce

s in

lo

w-g

rad

e in

flam

mat

ory

rea

ctio

n b

etw

een

ca

ses

and

co

ntr

ols

.

Th

e au

tho

rs s

ug

ges

t re

con

sid

erat

ion

of

the

clin

ical

ph

arm

aco

log

y o

f as

pir

in i

n d

iab

e-te

s.

Th

ey f

urt

her

ex

pla

in t

hat

th

e si

mil

arit

y o

f in

flam

mat

ory

mar

ker

s in

cas

es a

nd

con

tro

ls

ind

icat

es a

sim

ilar

ath

ero

scle

roti

c an

d in

-

flam

mat

ory

bac

kg

rou

nd

an

d s

ug

ges

ts t

hat

u

p-r

egu

lati

on

of

the

pla

tele

t re

spon

se i

s n

ot

mai

nly

rel

ated

to

dif

fere

nce

s in

vas

cula

r-in

flam

mat

ory

en

vir

on

men

t.

Rat

her

, an

up-

reg

ula

tio

n o

f p

late

let

resp

on

se a

pp

ears

to

be

du

e to

in

trin

sic

pla

tele

t al

tera

tio

n a

sso

ciat

ed

wit

h i

nsu

ffic

ien

t m

etab

oli

c co

ntr

ol.



www.icsi.org

99

Au

tho

r/

Yea

r D

esig

n

Ty

pe

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p

-val

ue,

co

nfi

den

ce

inte

rval

, re

lati

ve

risk

, o

dd

s ra

tio

, li

kel

iho

od

rati

o,

nu

mb

er n

eed

ed

to t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

Ser

ebru

-an

y, et

al.

, 2

00

8

PL

UT

O-

Dia

bet

es

Tri

al

RC

T

A

Ø

70

pat

ien

ts w

ith

do

cum

ente

d d

iab

etes

alr

ead

y

trea

ted

wit

h a

nte

ced

ent

asp

irin

wer

e ra

nd

om

ly

assi

gn

ed t

o r

ecei

ve

clo

pid

og

rel

and

81

mg

as-

pir

in o

r 8

1 m

g a

spir

in a

lon

e.

Th

e p

rim

ary

ob

ject

ive

of

this

stu

dy

was

to

co

mp

are

chan

ges

in

mu

ltip

le p

late

let

acti

va-

tio

n b

iom

ark

ers

wit

h 2

an

tip

late

let

stra

teg

ies

ov

er a

tre

atm

ent

per

iod

of

3 d

ays.

T

her

e w

ere

no

sig

nif

ican

t ch

ang

es f

rom

b

asel

ine

to 3

0 d

ays

in t

he

asp

irin

-alo

ne

gro

up

. I

n t

he

clo

pid

og

rel-

plu

s-as

pir

in g

rou

p,

ther

e w

as s

ign

ific

ant

inh

ibit

ion

of

pla

tele

t ac

tiv

ity

ass

esse

d b

y a

den

osi

ne

dip

ho

sph

ate

agg

reg

atio

n (

p=

0.0

00

1),

clo

sure

tim

e p

ro-

lon

gat

ion

(p

=0

.00

03

) an

d r

edu

ctio

n o

f p

late

-le

t ac

tiv

atio

n u

nit

s (p

=0

.00

01

) an

d e

xp

res-

sio

n o

f p

late

let/

end

oth

elia

l ce

ll a

dh

esio

n

mo

lecu

le (

p=

0.0

2),

gly

cop

rote

in a

nti

gen

(p

=0

.00

02

).

Th

e au

tho

rs c

on

clu

de

that

tre

atm

ent

wit

h

clo

pid

og

rel

and

asp

irin

fo

r 1

mo

nth

pro

-v

ides

sig

nif

ican

tly

gre

ater

in

hib

itio

n o

f p

late

let

acti

vit

y t

han

asp

irin

alo

ne

in p

a-ti

ents

wit

h t

yp

e 2

dia

bet

es.

Th

is i

s in

con

-tr

ast

to i

den

tica

lly

des

ign

ed s

tud

ies

in c

oro

-n

ary

art

ery

dis

ease

, p

ost

-str

ok

e o

r h

eart

fail

ure

pat

ien

ts w

ho

ex

hib

it l

ow

er r

esid

ual

p

late

let

acti

vat

ion

co

mp

ared

to

dia

bet

es p

a-ti

ents

.

Th

e im

pli

cati

on

s o

f th

is s

tud

y f

or

clin

ical

p

ract

ice

are

no

t ev

iden

t. It

can

no

t b

e de-

term

ined

fro

m t

his

sh

ort

stu

dy

wh

eth

er

mo

re p

ote

nt

anti

-pla

tele

t p

ote

ncy

wit

h

com

bin

atio

n t

her

apy

wil

l re

sult

in

bet

ter

ou

tco

mes

.

[Th

is s

tud

y i

s d

esi

gn

ed a

s a

pil

ot, s

o i

t is

no

t p

ow

ered

ad

equ

ate

ly t

o d

etec

t sm

all

dif

-

fere

nces

.]



www.icsi.org

100

Conclusion Grading Worksheet F – Annotations #28, 36 (Treatment with ACE Inhibitors or ARBs)


Work

Grou

p's

Con

clu

sion

: F

or

pat

ien

ts w

ith

ty

pe

2 d

iab

etes

mel

litu

s, A

CE

in

hib

ito

rs o

r A

RB

s ca

n r

edu

ce p

rog

ress

ion

of

mic

ro-

and

mac

rov

ascu

lar

com

pli

cati

on

s.

Con

clu

sio

n G

rad

e: I

Au

tho

r/

Yea

r

De-

sig

n

Ty

pe

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e,

con

fid

ence

inte

rval

, re

lati

ve r

isk

, o

dd

s ra

tio

, li

kel

iho

od

ra

tio

, n

um

ber

need

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

Wo

rk G

rou

p's

Co

mm

ents

(it

ali

cize

d)

Lew

is,

et

al.,

NE

JM,

20

01

RC

T

A

+

-1,7

15

pat

ien

ts (

30

-70

yea

rs)

fro

m 2

10

cl

inic

al

cen

ters

wit

h h

yp

erte

nsi

on

, n

eph

-ro

pat

hy

(u

rin

ary

pro

tein

ex

cret

ion

>8

99

m

g/2

4 h

ou

r), cr

eati

nin

e 1

.0-3

.0 m

g/d

L

(men

) o

r 1

.2-3

.0 m

g/d

L (

wo

men

), a

nd

ty

pe

2 d

iab

etes

-P

atie

nts

ran

do

mly

ass

ign

ed 3

00

mg

/day

o

f ir

bes

arta

n, 1

0 m

g/d

ay o

f am

lod

ipin

e,

or

pla

ceb

o

-Pat

ien

t, p

rov

ider

an

d d

ata

analy

sts

wer

e b

lin

ded

-Mean

fo

llo

w-u

p 2

.6 y

ears

-Pri

mar

y c

om

po

site

en

d p

oin

t (P

CE

): d

ou

bli

ng

bas

e-li

ne c

reati

nin

e, o

nse

t o

f E

SR

D (

dia

lysi

s, t

ran

spla

nta

-ti

on

or

creat

inin

e >

5.9

mg

/dL

), o

r d

eat

h f

rom

an

y

cau

se

-Car

dio

vas

cula

r co

mp

osi

te e

nd

po

int

(CC

E):

car

dio

-v

ascu

lar

dea

th, n

on-f

ata

l M

I, C

HF

req

uir

ing

hosp

ital

i-za

tio

n,

per

man

ent

neu

rolo

gic

al

def

icit

fro

m C

VA

, o

r lo

wer

lim

b a

mp

uta

tio

n a

bo

ve a

nk

le

-PC

E s

ho

wed

a 2

0%

rela

tiv

e ri

sk (

RR

) re

du

ctio

n f

or

irb

esar

tan

vs.

pla

ceb

o (

p=

0.0

06

) an

d a

23

% R

R r

educ-

tio

n f

or

irb

esar

tan

vs.

am

lod

ipin

e (

p=

0.0

06

)

-Th

ere

wer

e n

o s

ign

ific

ant

dif

fere

nce

s in

CC

Es

or

rate

s o

f d

eath

fro

m a

ny

cau

se b

etw

een

gro

up

s

-Th

e an

gio

ten

sin

-II-

recep

tor

blo

cker

ir

bes

arta

n i

s ef

fecti

ve

in p

rote

ctin

g

agai

nst

th

e p

rog

ress

ion

of

nep

hro

pa-

thy

du

e to

ty

pe

2 d

iab

etes

. T

his

pro

-

tect

ion

is

ind

epen

den

t o

f th

e re

du

cti

on

in

blo

od

pre

ssu

re i

t cau

ses.

Hea

rt O

ut-

com

es P

re-

ven

tio

n

Ev

alu

atio

n

(HO

PE

) S

tud

y I

n-

ves

tig

ato

rs,

Lan

cet

, 2

00

0

RC

T

A

+

-3,5

77

pat

ien

ts w

ith

dia

bet

es i

nclu

ded

in

th

e H

OP

E s

tud

y (

pati

ents

had

pre

vio

us

card

iov

asc

ula

r ev

ent

or

at l

east

on

e

oth

er c

ard

iov

asc

ula

r ri

sk f

acto

r, n

o

clin

ical

pro

tein

uri

a, h

eart

fai

lure

, o

r lo

w

ejec

tio

n f

racti

on

, an

d n

ot

tak

ing

AC

E

inh

ibit

ors

) -P

atie

nts

ran

do

mly

ass

ign

ed r

amip

ril

(10

mg

/day

) o

r p

lace

bo

, an

d v

itam

in E

o

r p

lace

bo

in

2 b

y 2

fac

tori

al d

esig

n

-All

pat

ien

ts a

ges

55

year

s o

f ag

e o

r

old

er

-4.5

-yea

r fo

llo

w-u

p

-Co

mb

ined

pri

mar

y o

utc

om

e: M

I, s

tro

ke a

nd

car

dio

-v

ascu

lar

dea

th

-Ram

ipri

l re

du

ced

th

e ri

sk o

f co

mb

ined

pri

mar

y o

ut-

com

e b

y 2

5%

(9

5C

I 1

2%

-36

%,

p=

0.0

00

4),

MI

by

22

%

(95

CI

6%

-36

%, p

=0

.01

), s

tro

ke

by

33

% (

95

CI

10

%-

50

%, p

=0

.00

74

), c

ard

iov

ascu

lar

deat

h b

y 3

7%

(9

5C

I 2

1%

-51

%, p

=0

.00

01

), t

ota

l m

ort

alit

y b

y 2

4%

(9

5C

I 8

%-3

7%

, p

=0

.00

4),

rev

ascu

lari

zati

on

by

17

% (

95

CI

2%

-30

%,

p=

0.0

31

), o

ver

t n

eph

rop

ath

y b

y 2

4%

(9

5C

I 3

%-4

0%

, p

=0

.00

04

), c

om

bin

ed p

rim

ary

outc

om

e b

y

25

% (

95

CI

12

-36

, p

=0

.02

7)

-Aft

er a

dju

stm

ent

for

chan

ges

in s

yst

oli

c a

nd

dia

sto

lic

blo

od

pre

ssu

res,

ram

ipri

l st

ill

low

ered

th

e r

isk

of

the

com

bin

ed p

rim

ary

ou

tco

me b

y 2

5%

(9

5C

I 1

2%

-36

%,

p=

0.0

00

4)

-Th

e st

ud

y w

as

sto

pp

ed 6

mo

nth

s ea

rly

beca

use

of

a co

nsi

sten

t b

enef

it o

f ra

mip

ril

com

par

ed t

o p

lace

bo

-Ram

ipri

l w

as b

enef

icia

l fo

r ca

rdio

-v

ascu

lar

even

ts a

nd

ov

ert

nep

hro

pat

hy

in

peo

ple

wit

h d

iab

ete

s.

Th

e c

ard

io-

vas

cula

r b

enef

it w

as g

reate

r th

an t

hat

attr

ibu

tab

le t

o t

he

dec

reas

e in

BP

.

Th

is t

reat

men

t re

pre

sen

ts a

vas

culo

-p

rote

cti

ve

and

ren

op

rote

ctiv

e e

ffect

fo

r p

eop

le w

ith

dia

bete

s.


www.icsi.org

101

Conclusion Grading Worksheet G – Annotations # 28, 36 (Thiazide Diuretics)


Wo

rk

Gro

up

's C

on

clu

sio

n:

Fo

r p

ati

ents

wit

h t

yp

e 2

dia

bet

es

mel

litu

s, t

hia

zide

diu

reti

cs i

n t

he

trea

tmen

t o

f h

yp

erte

nsi

on

can

red

uce

car

dio

-

vas

cula

r ev

ents

, p

arti

cula

rly

hea

rt f

ailu

re.

Co

nclu

sio

n G

ra

de:

I

Au

tho

r/

Yea

r D

e-si

gn

T

yp

e

Cla

ss

Qu

al-

ity

+

,–,ø

Po

pu

lati

on

Stu

die

d/S

am

ple

Siz

e P

rim

ary

Ou

tco

me M

eas

ure

(s)/

Res

ult

s (e

.g.,

p-v

alu

e, c

on

fi-

den

ce i

nte

rval,

rela

tiv

e ri

sk, o

dd

s ra

tio

, li

keli

ho

od

rati

o, n

um

-b

er n

eed

ed t

o t

reat)

Au

tho

rs' C

on

clu

sio

ns/

W

ork

Gro

up

's C

om

men

ts (

ita

lici

zed

)

An

tih

yp

er-

ten

siv

e an

d

Lip

id-

Lo

wer

ing

Tre

atm

ent

to P

rev

ent

Hea

rt A

t-

tack

Tri

al

(AL

LH

AT

)

Off

icer

s an

d

Res

earc

h

Gro

up

,

20

02

AL

LH

AT

tria

l

RC

T

A

+

-12

,06

3 p

atie

nts

wit

h t

yp

e 2

dia

-

bet

es

wit

h h

yp

erte

nsi

on

as

par

t o

f

a la

rge, m

ult

icen

ter

(62

3 N

ort

h

Am

eric

an c

ente

rs)

incl

ud

ing

a to

-

tal

of

33

,35

7 p

ati

ents

-Mean

ag

e 6

7 y

ears

-53

% m

ale;

47

% W

hit

e, 3

2%

Bla

ck, an

d 1

5%

His

pan

ic

-Mean

fo

llo

w-u

p 4

.9 y

ears

Am

lod

ipin

e 2

.5-1

0 m

gm

vs.

Ch

lort

ha

lid

on

e 1

2.5

-25

mg

m/d

-All

-cau

se m

ort

ali

ty:

rela

tiv

e ri

sk (

RR

) 0

.96

(9

5%

CI

0.8

2-

1.0

7)

-Str

ok

e: R

R 0

.9 (

95

%C

I 0

.75-1

.08

)

-Co

mb

ined

CV

dis

eas

e: R

R 1

.06

(9

5%

CI

0.9

8-1

.15

)

-An

y h

eart

fail

ure

: R

R 1

.42

(9

5%

CI

1.2

3-1

.64

)

Lis

ino

pri

l 1

0-4

0 m

gm

vs

Ch

lort

ha

lid

on

e 1

2.5

-25

mg

m/d

-All

-cau

se m

ort

ali

ty:

RR

1.0

2 (

95

%C

I 0

.91-1

.13

)

-Str

ok

e: R

R 1

.07

(9

5%

CI

0.9

-1.2

8)

-Co

mb

ined

CV

dis

eas

e: R

R 1

.08

(9

5%

CI

1.0

-1.1

7)

-An

y h

eart

fail

ure

: R

R 1

.22

(9

5%

CI

1.0

6-1

.42

)

-Fo

r ty

pe

2 d

iab

etic

pati

ents

, li

sino

pri

l

app

eare

d t

o h

ave n

o s

peci

al a

dv

anta

ge

(an

d a

mlo

dip

ine

no

sp

ecia

l d

etri

men

-

tal

effe

ct)

fo

r m

ost

CV

D o

utc

om

es

wh

en c

om

par

ed w

ith

ch

lort

hali

do

ne.

-Bec

au

se t

he

ma

in i

nte

nt

wa

s to

com

-

pa

re t

hia

zid

e, c

alc

ium

ch

an

nel

blo

cker

, a

nd

AC

E i

nh

ibit

or

trea

tmen

t,

the

ava

ila

ble

ste

p-u

p f

or

furt

her

ma

n-

ag

emen

t o

f h

yper

ten

sio

n f

or

pa

tien

ts

on

AC

E i

nh

ibit

ors

led

to

les

s th

an

typ

ica

l re

gim

en (

use

of

sym

pa

tho

lyti

cs

rath

er t

ha

n d

iure

tics

an

d c

alc

ium

cha

nn

el b

locke

rs).

S

ince

a l

arg

e p

ro-

po

rtio

n o

f d

iab

ete

s p

ati

ents

req

uir

e

mo

re t

ha

n o

ne

dru

g t

o c

on

tro

l th

eir

BP

, th

is s

tud

y s

ug

ges

ts t

ha

t a

diu

reti

c

sho

uld

be

inclu

ded

in

all

mu

ltid

rug

reg

imen

s.

Win

g e

t al.

,

20

03

AN

BP

2

Tri

al

RC

T

A

ø

-6,0

83

pat

ien

ts (

fro

m 1

,59

4 f

am-

ily

med

ical

pra

cti

ces

thro

ugh

ou

t

Au

stra

lia)

-On

ly 7

% w

ith

dia

bete

s

-95

% C

aucas

ian

-Mean

ag

e 7

2 y

ears

-Pat

ien

t g

rou

ps

wer

e eq

ual

at

ran

-

do

miz

atio

n, fo

llo

wed

fo

r 4

.1

yea

rs w

ith

in

ten

tio

n-t

o-t

reat

anal

ysi

s (0

.2%

lo

st t

o f

/u)

-En

ala

pri

l (A

CE

in

hib

ito

r) v

s. H

yd

roch

loro

thia

zid

e (d

iu-

reti

c)

-All

CV

ev

ents

or

deat

h f

rom

an

y c

ause

: H

azar

d r

ati

o (

HR

)

0.8

9 (

95

%C

I 0

.79

-1.0

0)

-Fir

st C

V e

ven

t o

r d

eat

h f

rom

an

y c

ause

: H

R 0

.89

(9

5%

CI

0.7

9-1

.01

)

-Dea

th f

rom

an

y c

ause

: H

R 0

.9 (

95

%C

I 0

.75-1

.09

)

-58

%-6

2%

rec

eiv

ing

tre

atm

ent

assi

gn

ed a

t th

e en

d o

f st

ud

y

and

eq

ual

BP

res

po

nse

(sy

sto

lic/

dia

sto

lic)

in

bo

th g

rou

ps

-in

po

st h

oc

analy

sis,

lar

gest

eff

ect

seen

in

male

pat

ien

ts

-In

itia

tio

n o

f an

tih

yp

erte

nsi

ve

trea

t-

men

t in

vo

lvin

g A

CE

in

hib

ito

rs i

n

old

er s

ub

jects

, p

arti

cula

rly

men

, ap

-

pea

rs t

o l

ead

to

bett

er o

utc

om

es

than

trea

tmen

t w

ith

diu

reti

c a

gen

ts, d

esp

ite

sim

ilar

red

uct

ion

s o

f b

loo

d p

ress

ure

.

-Th

ere w

as

a l

ow

er p

reva

len

ce o

f

dia

bet

es t

ha

n m

igh

t h

ave

been

ex-

pec

ted

(7

%)

mo

stly

beca

use

th

e s

tud

y

po

pu

lati

on

wa

s o

verr

epre

sen

ted

by

eld

erl

y C

au

casi

an

pa

tien

ts.

-Va

scu

lar

ou

tco

mes

an

d d

eath

wer

e

wo

rse

usi

ng

hyp

erte

nsi

ve r

egim

en

emp

ha

sizi

ng

hyd

roch

loro

thia

zid

e

com

pa

red

to

AC

E i

nh

ibit

ion

.

-Als

o,

insu

ffic

ien

t in

form

ati

on

is

pro

-

vid

ed t

o d

isce

rn w

het

her

gro

up

s w

ere

trea

ted

eq

ua

lly.

102


Support for Implementation:


Copyright © 2009 by Institute for Clinical Systems Improvement

This section provides resources, strategies and measurement specifications for use in closing the gap between current clinical practice and the recommendations set forth in the guideline.

The subdivisions of this section are:

• Priority Aims and Suggested Measures

• Key Implementation Recommendations

• Knowledge Resources

• Resources Available


www.icsi.org

103

Priority Aims and Suggested Measures

A multifactorial intervention targeting hyperglycemia and cardiovascular risk factors in individuals with diabetes is most effective. Both individual measures of diabetes care, as well as comprehensive measures of performance on broader sets of measures, are recommended. A randomized controlled trial has shown a 50% reduction in major cardiovascular events through a multifactorial intervention targeting hypergly-cemia, hypertension, dyslipidemia, microalbuminuria, aspirin and ACE inhibitor use in individuals with microalbuminuria (Gaede, 2003 [A]).

Goals for A1c, low-density lipoprotein and other diabetes measures should be personalized, and lower goals for A1c and low-density lipoprotein than those included here in the priority aims and measures may be clinically justified in some adults with type 2 diabetes. However, efforts to achieve lower A1c below 7% may increase risk of mortality, weight gain, hypoglycemia and other adverse effects in many patients with type 2 diabetes. Therefore, the aims and measures listed here are selected carefully in the interests of patient safety.

1. Diabetes Optimal Care Measures: Maximize the percentage of adult patients, ages 18-75 with type 2 diabetes mellitus, who in a defined period of time achieve any of the following measures of established control:

Possible measures for accomplishing this aim:

a. Percentage A1c less than 8%

b. Percentage on a statin

c. Percentage with LDL less than 100 mg/dL

d. Percentage of type 2 diabetes patients with blood pressure measured in last year and most recent BP less than 130/80 mmHg

e. Percentage of type 2 diabetes patients who are current documented non-smokers

f. Percentage of type 2 diabetes patients ages 41-75 with type 2 diabetes mellitus and with coronary artery disease (CHD, defined as one or more ICD-9 codes for CHD listed at ncqa.org) who take daily aspirin or another antiplatelet medication

Notes to diabetes optimal care measures:

1a. A1c measure: The A1c goal for type 2 diabetes patients should be personalized. The optimal clinical A1c goal for many diabetes patients is lower than 8% (see Annotation # 11).

1c. Low-density lipoprotein measure: The optimal clinical low-density protein goal for some patients with diabetes, such as those with coronary artery disease, may be lower than 100 mg/dL. Patients who are or may become pregnant should not use most lipid-lowering agents including statins. The benefit of low-density protein reduction is less in younger than in middle-aged or older patients with type 2 diabetes.

1f. Aspirin measure: This recommendation is subject to modification on the basis of clinical trials that are expected to report their findings in the next year.



www.icsi.org

104

2. Diabetes Optimal Care Comprehensive Measure Set: Maximize the percentage of adult patients ages 18-75 with type 2 diabetes mellitus, who in a one-year period of time achieve each of the following measures of care.


a. Percentage with A1c less than 8%

b. Percentage with LDL less than 100 mg/dL

c. Percentage with blood pressure measured in last year and most recent blood pressure less than or equal to 130/80 mmHg

d. Percentage who are current documented non-smokers.

Notes to diabetes optimal care comprehensive measures:

All-or-none approach of process quality yields a picture quite different from either the item-by-item approach or the composite approach (Nolan, 2006 []). All or none more closely reflects the interests and likely desires of the patient.

2a. A1c measure: The A1c goal for type 2 diabetes patients should be personalized. The optimal clinical A1c goal for many diabetes patients is lower than 8% (see Annotation #11).

2b. Low-density protein measure: The optimal clinical low-density protein goal for some patients with diabetes, such as those with coronary artery disease, may be lower than 100 mg/dL. Patients who are or may become pregnant should not use most lipid-lowering agents including statins. The benefit of low-density protein reduction is less in younger than in middle-aged or older patients with type 2 diabetes.

3. Diabetes Process of Care Measure Set: Maximize the percentage of adult patients ages 18-75 with type 2 diabetes mellitus for whom recommended screening procedures are done.


a. Percentage of patients with type 2 diabetes mellitus with A1c test in the last 12 months.

b. Percentage of patients with type 2 diabetes mellitus receiving a lipid profile in the last 12 months.

c. Percentage of patients with type 2 diabetes mellitus receiving one or more blood pressure measure-ments in the last 12 months.

d. Nephropathy screening rate: DENOMINATOR: Include those patients with type 2 diabetes mellitus who are either (a) not on an ACE or ARB medication OR (b) not diagnosed with chronic kidney disease. NUMERATOR: Those who are included in the denominator who have one or more microalbuminuria tests within the last 12 months. (Suitable tests include CPT Codes such as 820.43 ["urine, microalbumin, quantitative"], or 841.55 ["protein; total, except refractometry"]).

e. Retinopathy screening rate: percentage of patients with type 2 diabetes mellitus with dilated eye exam within the last 24 months. The nature of the exam is not specified and may be completed by an ophthalmologist or optometrist.

f. Foot care screening rate: percentage of patients with type 2 diabetes mellitus with a comprehensive foot exam documented in the last year (HEDIS, 2009).

g. Diabetes process of care comprehensive measure: percentage of patients with type 2 diabetes, age 18-75 with type 2 diabetes mellitus, for whom all the recommended screening procedures (3a to 3f above) were done in the indicated time frames.

Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Priority Aims and Suggested Measures Thirteenth Edition/May 2009


www.icsi.org

105

Notes to diabetes process of care measure set:

3e. Retinopathy screening intervals should be personalized to the patient. Some patients, especially those with elevated A1c or blood pressure, or with a previously abnormal retinal exam, may benefit from shorter screening intervals.

3g. Unlike the Diabetes Optimal Measures, there is no upper limit recommended on appropriate levels of performance on the Diabetes Process of Care Measure Set.

4. High-Risk Population Measures: The purpose of this aim is to identify and focus on a higher risk population by decreasing the percentage of adult patients, ages 18-75 with type 2 diabetes mellitus, with poorly controlled glucose and cardiovascular risk factors (clinical strategies that target high-risk populations may be more viable with limited resources).


a. Percentage of patients with type 2 diabetes mellitus with Alc test in the last year greater than 9%. (HEDIS, 2009)

b. Percentage of patients with type 2 diabetes mellitus with low-density lipoprotein test in the last year greater than 130 mm/dL.

c. Percentage of patients with type 2 diabetes mellitus with blood pressure greater than 140/90 mmHg.

d. Percentage of patients with type 2 diabetes mellitus with A1c greater than 9% or low-density lipopro-tein greater than 130 Mg/dL or blood pressure greater than 140/90 mmHg (high-risk comprehensive measures).

e. Percentage of patients with type 2 diabetes mellitus who are active smokers.

At this point in development for this guideline, there are no specifications written for possible measures listed above. ICSI will seek input from the medical groups on what measures are of most use as they implement the guideline. In a future revision of the guideline, measurement specifications may be included.

Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Priority Aims and Suggested Measures Thirteenth Edition/May 2009


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106

Key Implementation Recommendations

The implementation of type 2 diabetes mellitus clinical guidelines at medical groups and clinics is a complex and challenging task. However, a number of key processes have been shown to accelerate effective clinical guideline implementation and care improvement (Sperl-Hillen, 2005 [D]). These overlapping care elements can be categorized at the medical group and provider levels:

• Essential Elements at the Medical Group Level:

- Leadership. Medical group leaders must communicate the need for change in clinical practice patterns and consistently identify improvement priorities.

- Resources. Resources adequate to the task at hand will be needed to assure the success of a change effort. Resources may include staff time, money and provision of tools (such as elec-tronic medical records) to support care improvement.

- Select Specific Improvement Goals and Measures. For most chronic diseases, including diabetes, the most efficient improvement strategy is to focus on a limited number of specific improvement goals. These may be based on observed gaps in care, potential clinical impact, cost considerations or other criteria (O'Connor, 2005a [D]). In type 2 diabetes, focusing on glycemic control, lipid control and blood pressure control is a strategy that has been shown to be effective in preventing up to 53% of heart attacks and strokes, the leading drivers of excess mortality and costs in adults with diabetes (Gaede, 2003 [A]).

- Accountability. Accountability within the medical group is a management responsibility, but external accountability may also play an important enhancing role to motivate sustained efforts to implement guidelines and improve care. Examples of external accountability include participation in shared learning activities (such as Institute for Healthcare Improvement or ICSI and its action groups), or public reporting of results (such as in pay-for-performance or the Minnesota Community Measures Project).

- Prepared Practiced Teams. The medical group may need to foster the development of prepared practice teams that are designed to meet the many challenges of delivering high-quality chronic disease care.

• Essential Elements at the Clinic Level:

- Develop "Smart" Patient Registries. These are registries that are designed to identify, automatically monitor, and prioritize patients with diabetes based on their risk, current level of control, and possibly patient readiness-to-change.

- Assure "Value-Added" Visits. These are office visits or other patient encounters (by phone, e-mail, etc.) that include intensification of treatment if the patient has not yet reached his/her evidence-based clinical goals. Failure of providers and patients to intensify treatment when indicated (referred to as "clinical inertia") is a key obstacle to better diabetes care (O'Connor, 2003 [R]; O'Connor, 2005a [R]; O'Connor, 2005b [R]). HSR editorial. Previsit planning and best practice prompts may help to increase the efficiency of patient visits and remind providers of needed tests and care.

- Develop "Active Outreach." These are strategies to reach patients with chronic disease who have not returned for follow-up or for other selected elements of care. Outreach strategies that enhance the likeliness of a future provider encounter that addresses one of the barriers to patient activation (discussed below) may be more effective. Simple reporting of lab test results or care suggestions through the mail may be ineffective at addressing these barriers.



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- Emphasize "Patient Activation" Strategies. These may include diabetes education and other actions designed to sustain engagement of patients with their diabetes care. Many patients with diabetes either (a) do not really believe they have diabetes, or (b) do not really believe that diabetes is a serious disease, or (c) lack motivation for behavioral change, or (d) do not believe that recommended treatments will make a difference to their own outcomes. For care to be effective, these issues must be addressed for many patients (O'Connor, 1997 [D]).

Knowledge Resources

Criteria for Selecting ResourcesThe following resources were selected by the Diagnosis and Management of Type 2 Diabetes Mellitus in Adults guideline work group as additional resources for providers and/or patients. The following criteria were considered in selecting these resources.

• The site contains information specific to the topic of the guideline.

• The content is supported by evidence-based research.

• The content includes the source/author and contact information.

• The content clearly states revision dates or the date the information was published.

• The content is clear about potential biases, noting conflict of interest and/or disclaimers as appropriate.

Resources Available to ICSI Members OnlyICSI has a wide variety of knowledge resources that are only available to ICSI members (these are indicated with an asterisk in far left-hand column of the Resources Available table). In addition to the resources listed in the table, ICSI members have access to a broad range of materials including tool kits on CQI processes and Rapid Cycling that can be helpful. To obtain copies of these or other Knowledge Resources, go to http://www.icsi.org/improvement_resources. To access these materials on the Web site, you must be logged in as an ICSI member.

The resources in the table on the next page that are not reserved for ICSI members are available to the public free-of-charge.

Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Key Implementation Recommendations Thirteenth Edition/May 2009


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Resources Available


* Available to ICSI members only.

* Author/Organization Title/Description Audience Web Sites/Order InformationAmerican DiabetesAssociation

American Diabetes Association:The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.

All About Diabetes

Patients and Families

http://www.diabetes.org/about-diabetes.jsp1-800-232-6733

American DiabetesAssociation

American Diabetes Association: The mission of the association is to prevent and cure diabetes and to improve the lives of all people affected by diabetes.

Basic Carbohydrate Counting (booklet)


http://www.diabetes.org/shop-for-books-and-gifts.jspAmerican Drug Administration #S623-011-800-232-6733



Complete Guide to Diabetes (book)


http://www.diabetes.org/shop-for-books-and-gifts.jspAmerican Drug Administration #4809-04;1-800-232-6733



Complete Guide to Carbohydrate Counting (booklet)


http://www.diabetes.org/shop-for-books-and-gifts.jspAmerican Drug Administration #4715-021-800-232-6733



Complete Guide to Diabetes (book)


http://www.diabetes.org/shop-for-books-and-gifts.jspAmerican Drug Administration #4809-04;1-800-232-6733


American Diabetes Association and American Dietetic Association: The mission of the associations are to prevent and cure diabetes and to improve the lives of all people affected by diabetes.

Exchange Lists for Meal Planning (pamphlet)


http://www.diabetes.org/nutrition-and-recipes/nutrition/exchangelist.jsp1-800-232-6733


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Diagnosis and Management of Type 2 Diabetes Mellitus in Adults Resources Available Thirteenth Edition/May 2009


* Author/Organization Title/Description Audience Web Sites/Order InformationAmerican DiabetesAssociation


Healthy Food Choices (pamphlet)


http://www.diabetes.org/nutrition-and-recipes/nutrition/healthyfoodchoices.jsp1-800-232-6733#5903-03 (English)#5903-13 (Spanish)



Wide variety of information on diabetes as well as recent publications; series of journals for both consumers and health professionals; community resources.

Patients and Families; Health Care Professionals

http://www.diabetes.org

Centers for DiseaseControl and Prevention

Centers for Disease Control and Prevention: Educational materials in Spanish as well as English, and low literacy public health and community campaigns for educating about diabetes and diabetes prevention.


http://www.cdc.gov/diabetes

HealthFinder HealthFinder: A-Z health information organizations and health care topics.


http://www.healthfinder.gov

* ICSI Chronic Care Action Group Summary 2002: ICSI Action Group/Redesign Collaborative Summary Reports are designed to describe key activities conducted in a collaborative while highlighting results achieved by participating member organizations.

Health Care Professionals

http://www.icsi.org

* ICSI Chronic Care Action Group Summary 2003: ICSI Action Group/Redesign Collaborative Summary Reports are designed to describe key activities conducted in a collaborative while highlighting results achieved by participating member organizations.


http://www.icsi.org

* ICSI Continual Improvement Collabora-tive within the Disease Management Strategy Program at Mayo Clinic, Rochester: Describes Mayo Clinic's approach to utilizing teams to imple-ment health care guidelines & improve care to patients. (12/99)


http://www.icsi.org


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* Author/Organization Title/Description Audience Web Sites/Order Information* ICSI Diabetes Action Group 1997-2005

Summary: ICSI Action Group/Rede-sign Collaborative Summary Reports are designed to describe key activities conducted in a collaborative while highlighting results achieved by partici-pating member organizations.


http://www.icsi.org

* ICSI Diabetes Education Program – Patient Survey at HealthEast: HealthEast implemented a Diabetes Education Program to increase patient self-management of diabetes. Feedback was solicited from patients to identify the types of education & follow-up they needed to manage their diabetes. (12/99)


http://www.icsi.org

* ICSI Diabetes Patient Registries: Three Medical Groups' Experience:HealthEast Clinics, HealthPartners Medical Group and Mayo Clinic have developed a patient registry to improve management of diabetes care. This report explores how these three groups are using the registry to best use and design criteria for the registry. (3/01)


http://www.icsi.org

ICSI Translation for Patients of the ICSI Type 2 Diabetes Mellitus guideline (guideline)


(952) 814-7060 orhttp://www.icsi.org

International Diabetes Center

International Diabetes Center:International Diabetes Center at Park Nicollet has provided world-class dia-betes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.

Blood Glucose Patterns (booklet)


http://www.idcpublishing.comIDC #2058-816A


International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class diabetes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.

Carbohydrate Counting Booklet


http://www.idcpublishing.comIDC #2058-802



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* Author/Organization Title/Description Audience Web Sites/Order InformationInternational Diabetes Center


Exchanges for All Occasions - Pocket Edition (book)


http://www.idcpublishing.comIDC #2058-EAOP



Fast Food Facts - Pocket Edition (book)





Healthy Eating (booklet)


IDC#2058-814 (English)#2058-821 (Spanish)



Managing Type 2 Diabetes (book)





My Food Plan (pamphlet)


http://www.idcpublishing.comIDC#2058-25 (English)#2058-823 (Spanish)




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* Author/Organization Title/Description Audience Web Sites/Order InformationInternational Diabetes Center


My Insulin Plan (pamphlet)





Record booklet





Safe and Healthy Exercise (booklet)


http://www.idcpublishing.comIDC-2058-805


International Diabetes Center: International Diabetes Center at Park Nicollet has provided world-class dia-betes care, education, publications and research programs that have met the needs of people with diabetes and their families since 1967.

Staying Healthy with Type 2Diabetes (booklet)


http://www.idcpublishing.comIDC#2058-824 (English)#2058-825 (Spanish)



Type 2 Diabetes Basics (client book)


http://www.idcpublishing.comIDC-2058-BCBK



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* Author/Organization Title/Description Audience Web Sites/Order InformationLabat & Maggi Weight Management for Type II

Diabetes (book)Patients and Families

pub. by Wiley & SonsISBN #0471347507

Mayo Clinic Mayo Clinic: Disease and Condition Centers Information and tools to help you manage a chronic disease or condi-tion.


http://www.mayoclinic.com

Minnesota Community Measurement

The D5.org

The D5 is a set of five treatment goals that, when achieved together, repre-sent the gold standard for managing diabetes. Reaching all five goals greatly reduces a patient's risk for the cardio-vascular problems associated with diabetes.


http://www.theD5.org

National Institutes of Diabetes, Digestive and Kidney Diseases

National Institute of Diabetes, Digestive and Kidney Diseases: Data, statistics, information for health professionals, educational materials in Spanish as well as English, and low literacy.

This Web site is a division of the National Institutes of Health.


http://www.niddk.nih.gov

Also, links to NDEP, NKDEP, NIDDK

National Institutes of Health

National Institutes of Health: This user-friendly site helps you start a search for health information by directing you to some credible data-bases.


http://www.nih.gov

* Park Nicollet Health Services

Diabetes, What You Need To Know: Provided by Park Nicollet Health Services (brochure)


http://www.icsi.org

Protocol DrivenHealthcare

Protocol Driven Healthcare: Self-management interactive site, informa-tion on diabetes and managing it, chat rooms, capacity to e-mail for questions.


http://www.mydiabetes.com

Staywell/Krames Diabetes and Exercise (brochure) Patients and Families

1-800-333-3032



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* Author/Organization Title/Description Audience Web Sites/Order InformationThe Food and Nutrition Information Center

The Food and Nutrition Informa-tion Center: Sponsored by the United States Department of Agriculture (USDA), this site is user friendly and filled with current information on almost any nutrition topic.


http://www.nal.usda.gov/fnic/

WebMD Corporation Web MD: Wide variety of informa-tion on diabetes as well as recent publications; series of journals for both consumers and health professionals; clinical resource for providers, and education materials that providers can download for their patients.


http://www.webMD.com
